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Stem cell case studies

Read our stem cell case studies to discover how umbilical cord cells have been used to treat conditions such as leukaemia, stroke, brain injury and autism.

Since 1988, cord blood stem cells have been used to treat a growing number of diseases and disorders.

The first transplant was for a 5-year-old boy called Matthew Farrow, who received his sister’s cord blood to treat Fanconi anaemia. Children with the condition are only expected to live into their teenage years, but Matthew is now a healthy 30-year-old with a family of his own.

Fanconi anaemia is just one of more than 80 potential diseases cured by cord blood and in the past three decades, there have been more and more stem cell success stories from all around the world. You can find out more about these case studies below.

Jay’s journey

In 2016, little Jay Shetty took part in a pioneering clinical trial for cerebral palsy at Duke University in the USA. After he was diagnosed with cerebral palsy at a young age, his parents decided to store his brother’s stem cells with Cells4Life .

In 2017, Jay received those cells in a single injection that was overseen by Dr Joanne Kurtzberg from Duke’s medical centre.

“His muscle rigidity has reduced, and his vision has improved,” says Jay’s mother, Shilpa. “We definitely noticed a difference.”

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Case report: Stem cells a step toward improving motor, sensory function after spinal cord injury

Susan Barber Lindquist

Stem cell-based therapy for COVID-19 and ARDS: a systematic review

Gabriele Zanirati ORCID: orcid.org/0000-0002-1986-973X 1 , 2 ,
Laura Provenzi ORCID: orcid.org/0000-0001-9356-5016 1 , 3 ,
Lucas Lobraico Libermann 1 , 3 ,
Sabrina Comin Bizotto 1 , 3 ,
Isadora Machado Ghilardi 1 , 2 ,
Daniel Rodrigo Marinowic 1 , 2 , 3 ,
Ashok K. Shetty ORCID: orcid.org/0000-0001-5049-6671 4 &
Jaderson Costa Da Costa ORCID: orcid.org/0000-0001-6776-1515 1 , 2 , 3

npj Regenerative Medicine volume 6 , Article number: 73 ( 2021 ) Cite this article

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Respiratory tract diseases
Stem-cell research
Stem-cell therapies
Viral infection

Despite global efforts to establish effective interventions for coronavirus disease 2019 (COVID-19) and its major complications, such as acute respiratory distress syndrome (ARDS), the treatment remains mainly supportive. Hence, identifying an effective and safe therapy for severe COVID-19 is critical for saving lives. A significant number of cell-based therapies have been through clinical investigation. In this study, we performed a systematic review of clinical studies investigating different types of stem cells as treatments for COVID-19 and ARDS to evaluate the safety and potential efficacy of cell therapy. The literature search was performed using PubMed, Embase, and Scopus. Among the 29 studies, there were eight case reports, five Phase I clinical trials, four pilot studies, two Phase II clinical trials, one cohort, and one case series. Among the clinical studies, 21 studies used cell therapy to treat COVID-19, while eight studies investigated cell therapy as a treatment for ARDS. Most of these (75%) used mesenchymal stem cells (MSCs) to treat COVID-19 and ARDS. Findings from the analyzed articles indicate a positive impact of stem cell therapy on crucial immunological and inflammatory processes that lead to lung injury in COVID-19 and ARDS patients. Additionally, among the studies, there were no reported deaths causally linked to cell therapy. In addition to standard care treatments concerning COVID-19 management, there has been supportive evidence towards adjuvant therapies to reduce mortality rates and improve recovery of care treatment. Therefore, MSCs treatment could be considered a potential candidate for adjuvant therapy in moderate-to-severe COVID-19 cases and compassionate use.

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Introduction.

In January 2020, to raise awareness internationally and to prevent further viral spread, the World Health Organization (WHO) declared the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) outbreak a public health emergency 1 . The virus responsible for coronavirus disease 2019 (COVID-19) infected more than 128.7 million people around the world by March 2021 2 . Despite global efforts to establish effective interventions for COVID-19, its treatment remains mainly supportive, and one of the major complications of the disease, acute respiratory distress syndrome (ARDS), poses a significant challenge 3 .

Coronaviruses that are responsible for severe respiratory syndrome (SARS) and the Middle East respiratory syndrome (MERS) belong to the same beta coronavirus genus, and SARS and MERS resemble SARS-CoV-2 symptoms 4 . Novel therapeutic approaches have been developed to treat COVID-19 complications, especially ARDS, some of which exploit antiviral and immune-based mechanisms 5 . More recently, a significant number of cell-based therapies have been through clinical investigation, involving, most importantly, mesenchymal stem cells (MSCs) and MSC-derived conditioned media or extracellular vesicles. These therapies have multiple therapeutic targets because MSCs can release a variety of soluble mediators, but their safety and potential efficacy are still to be determined 6 .

Specifically, MSCs secrete keratinocyte growth factor, prostaglandin E2, granulocyte-macrophage colony-stimulating factor, and cytokines such as IL-6 and IL-13, that can influence how immune cells—both innate and adaptive—interact with the cellular environment. These soluble factors can promote alveolar macrophage phagocytosis and alter the cytokine profile released by immune cells. Such functions are expected to be effective against the respiratory infections discussed here 7 .

Considering the limited availability of effective therapies for COVID-19 and one of its complications ARDS, new therapeutic approaches are urgently needed. In this context, cell-based therapies can be an attractive alternative because of their accessibility and relative safety. Although the use of MSCs as immune therapy has been regarded as safe, a meta-analysis found fever as the predominant adverse event associated with MSC therapy. Notably, no acute infusion toxicities, infections, thrombotic/embolic events, or malignancy were found 8 . Here, we systematically reviewed studies that investigated different types of cells as a treatment for the respiratory diseases mentioned above.

Study characteristics

The initial search of the databases identified a total of 1347 potentially relevant records. After excluding duplicates, 1114 articles remained, and titles and abstracts of the remaining records were scanned as part of a new screening according to inclusion and exclusion criteria previously established. Four gray literatures were also analyzed. A total of 1077 articles were excluded based on the exclusion criteria. The remaining 37 articles that met the inclusion criteria were thoroughly examined. Among these, eight were excluded, and the remaining 29 were included for the review. The PRISMA flow diagram (Fig. 1 ) illustrates the selection process of the studies for systematic review.

Summary of evidence search and study selection.

Among the clinical studies, 17 of them reportedly applied cell therapy to treat COVID-19, while the remaining eight studies investigated cell therapy as a treatment for ARDS. Additionally, four clinical COVID-19 articles were included as gray literature, bringing the total of selected clinical studies to 29. None of the included articles applied cell therapy to MERS or SARS-CoV-1.

The clinical and study characteristics are described in Table 1 .

Study designs and evidence levels

Among the 29 included clinical studies, there were eight case reports (27.5%), five Phase I clinical trials (17.2%), four (13.7%) pilot studies, two Phase II clinical trials (6.8%), one cohort (3.4%), and one case series (3.4%). The study designs and classification of evidence are described in Table 2 .

It should be noted that eight (27.5%) studies used cell therapy as compassionate use and one (3.4%) as a proof of concept. Most studies (75%) used mesenchymal stem cell therapy in an attempt to treat COVID-19.

The articles were categorized based on levels of scientific evidence following the Oxford Center for Evidence-Based Medicine Classification 9 and the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) 10 .

According to the Oxford Center for Evidence-Based Medicine Classification 9 , of the 29 included articles, five were classified as grade A recommendations; within these, two (6.8%) were 1 A, and three (10.3%) were 1B. Among grade B recommendations, there were 14 studies. The levels of evidence were eight (27.5%) 2B and six (20.6%) 2 C. Among grade C recommendations, ten (34.4%) articles were classified as level 4 evidence.

According to the GRADE 10 , of the 29 included articles, two (6.8%) were considered high evidence level, three (10.3%) moderate, fourteen (48.2%) low, and ten (38.4%) minimal evidence level.

Patient characteristics

Clinical studies using cell therapy for the treatment of COVID-19 patients were performed in five different countries. Following are the total numbers of patients by country from all 29 studies: China ( n = 238), the United States ( n = 30), Spain ( n = 13), Iran ( n = 11), and Germany ( n = 23). Clinical studies that investigated ARDS included patients from the United States ( n = 96), the United Kingdom ( n = 30), China ( n = 20), Sweden ( n = 5), Mexico ( n = 5), and South Korea ( n = 1). Age of the patients ranged from 19 to 86 years.

Intervention characteristics

Among the 29 selected clinical articles, eleven types of umbilical cord MSCs were analyzed. The cell types investigated in the studies comprised (1) human umbilical cord MSCs 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , (2) cardiosphere-derived MSCs 22 , (3) human bone marrow MSCs (hBM-MSCs) 23 , 24 , 25 , 26 , 27 , 28 , (4) extracellular vesicles derived from BM-MSCs 29 , (5) autologous peripheral blood-derived mononuclear cells (PBMCs) 30 , (6) human adipose tissue-derived MSCs 31 , 32 , (7) allogeneic bone marrow-derived multipotent adult progenitor cells (MAPC) expanded ex vivo 33 , (8) ACE2-MSCs 34 , (9) human menstrual blood-derived MSCs 35 , 36 , (10) immunity‐and matrix-regulatory cells (IMRCs) 37 , and (11) MSCs derived from perinatal tissues 38 .

Main parameters

A total of five groups of readouts—all of them subdivided into several parameters—were identified among the clinical studies. Laboratory measurements were common to 25 out of the 29 clinical articles, representing 86.2% of our study sample. The cited parameters included standard laboratory measurements, such as lymphocyte count, COVID-19 PCR test, basic metabolic panel (BMP) and levels of procalcitonin, ferritin, angiopoietin, d-dimer, bilirubin, alanine aminotransferase (ALT), creatinine, CKMB, cardiac troponin, and immune system parameters, such as IL-6, IL-8, IL-1ɑ, IL-1β, TNF-ɑ, and IL-1. Twenty studies, which correspond to 68.9% of the included studies, investigated pulmonary function using various parameters and exams, such as chest X-ray, bronchoscopy, chest CT, lung compliance, lung injury score (LIS), and the following biomarkers: receptor for advanced glycation end-product (AGER), which is a marker for lung epithelial injury, and angiopoietin-2 (ANGPT2), a marker for endothelial injury. All studies evaluated adverse reactions, safety, and mortality after the intervention. Ten studies (34.4%) analyzed the relationship between cell therapy and the discontinuation of ventilator support. Furthermore, eight studies (27.5%) documented additional data, such as mental status, patient’s physical capacity, health-related quality of life (HRQoL) assessment, e electrocardiogram (EKG), viral load, blood type and screen, blood culture, urine culture, and body mass index (BMI).

Main outcomes

Among the 14 studies that evaluated lymphocyte counts before and after cell therapy, 12 reported a statistically significant elevation in lymphocyte numbers (85.7%). Fourteen of the seventeen studies which assessed CRP levels reported a decrease in this parameter (82.3%). As for plasma cytokines, cell therapy was found to reduce IL-6 levels in nine (52.9%) out of seventeen studies that investigated this parameter. TNF-α levels decreased in five out of seven studies (71.4%) that assessed its posttreatment values. Five out of six studies that measured ferritin reported a significant reduction after cell infusion, while six out of eight studies (75%) reported a D-dimer decrease. Remarkably, all studies that evaluated the following pulmonary parameters reported a statistically significant difference between pre- and post-cell therapy results: there was an increase in PaO2/FIO2 ratio in 12 out of 14 articles (85.7%), an increase in oxygen saturation in 50% of the articles and an improvement on lung image—chest CT or chest radiography—in 15 out of 17 studies (88.2%). Eighteen studies assessed symptoms at admission and clinical status after cell therapy, and all of them reported clinical improvement. Additionally, 11 out of 14 studies (78.5%) demonstrated discontinuation of oxygen support (intubation and ECMO) after cell infusion at a statistically significant rate. Nine studies reported a reduction in mortality, but two of them did not report a significant reduction (77.7%). Six studies evaluated and reported improvement in the duration of hospitalization. The primary outcomes and evaluated parameters are summarized in Table 3 .

Evidence level: 1A and 1B studies

Studies in higher evidence level categories (1A and 1B) described some noteworthy findings. In a randomized phase 2 safety trial for patients with moderate-to-severe ARDS, Matthay et al. revealed a decrease in endothelial injury ascertained by reduced plasma concentrations of ANGPT2 in the MSC-treated patients versus the control group 27 . They also reported that after MSC therapy, there was a trend towards a decreased number of ventilator-free and organ failure-free days and improved oxygenation index, although not significantly 27 . Notably, the number of intensive care-free days was found to be statistically relevant. Additionally, they showed a reduction in the levels of CRP and ANGPT2 biomarkers 27 .

Shi and colleagues performed a multicenter, randomized placebo-controlled phase 2 efficacy trial with 100 severe COVID-19 patients, who either received placebo ( n = 35) or umbilical cord mesenchymal stem cells (UC-MSC) infusion ( n = 65) alongside the common care treatments. Supplementary oxygen was necessary for 44 (67.69%) patients from the treatment group and for 23 (65.71%) patients from the placebo group. They noticed that UC-MSC infusions could reduce the proportion of abnormal lung lesions, especially lesions with solid appearance, compared to placebo. In this study, MSCs led to a decrease in ground-glass lesions; however, it was not significant compared to the placebo group 19 . Both articles classified 1 A according to Oxford and GRADE systems described that cell therapy was a safe and well-tolerated alternative 19 , 27 . All three papers classified as 1B also concluded that the procedure was safe 14 , 31 , 33 . Zheng et al. in a single-center, randomized, double-blind, placebo-controlled trial in which 12 patients with moderate-to-severe ARDS were arbitrarily assigned to receive either allogeneic adipose-derived humans MSCs or placebo. They observed that the MSC group displayed a significant improvement in oxygenation index, compared to baseline values—but not compared to placebo. Parameters such as ventilator-free and ICU-free days and serum IL-6 and IL-8 levels did not show a difference when the baseline values were compared to predetermined time points 31 . Bellingan et al. reported that MSCs reduced mortality and increased ventilator-free and ICU-free days compared to placebo 33 . Lanzoni et al. conducted a controlled, double-blinded, randomized phase 1/2a clinical trial to determine the safety and efficacy of UC-MSC infusion in 24 patients with COVID-19 ARDS. The subjects were divided into a UC-MSC infusion ( n = 12) and a placebo ( n = 12) group. They noticed that UC-MSC infusion significantly contributed to improved patient survival and time of recovery. This study also reported a significant decrease in the following inflammatory cytokines after treatment: GM‐CSF (pro-inflammatory M1 macrophage phenotype inducer), IFN-γ, IL‐5, IL‐6, IL‐7, TNF-α, TNF- β, and others 14 .

Evidence level 2B and 2C studies

Wilson and associates conducted a study to assess the safety and the maximally tolerated dose of MSCs - up to 10 million cells/kg predicted body weight (PBW). The study was a multicenter, open-label, non-randomized, noncontrolled phase 1 clinical trial, in which nine patients were equally subdivided into three intervention groups: low dose MSCs (1 million cells/kg PBW), an intermediate dose MSCs (5 million cells/kg PBW), and the high dose MSCs (10 million cells/kg PBW). After the treatment, the concentrations of several biomarkers (IL-6, IL-8, AGER, and ANGPT2) were decreased when compared between the baseline and day 3 values 31 , 33 . However, it is not possible to relate these findings to the previously reported changes in biomarkers, due to the lack of a matched control group with the MSCs treatment group in this study.

Hashemian and collaborators performed a multicenter, open-label, non-randomized, noncontrolled trial, with 11 subjects that either received freeze/thawed UC-MSCs ( n = 6) or fresh PL-MSCs ( n = 11). They noted that inflammatory biomarkers (CRP, IL-6, IL-8, and TNF-α) were significantly decreased after the MSC infusions. Notably, the anti-inflammatory cytokines IL-4 and IL-10 levels were also increased in four cases. Moreover, the study reported that nine (81.81%) treated patients tolerated the MSCs infusions 38 .

In a pilot study, Leng et al investigated the early efficacy of MSC therapy in seven patients with COVID-19 pneumonia along with the placebo treatment in three patients. Two days after infusions, they found improvements in pulmonary function, decreased levels of CRP and inflammatory cytokines, and augmented IL-10 concentration and regulatory DC cells 34 .

Meng F. et al. conducted a controlled, non-randomized, phase 1 clinical trial to evaluate the safety of human umbilical cord-derived MSC infusions in 18 patients. They observed that four patients displaying the highest levels of IL-6 showed a substantial decrease within 3 days of the treatment, but no such trend was observed in patients with low plasma IL-6. Regarding the PaO2/FiO2 ratio, there were improvements in most of the severe patients. Additionally, there was a decline in concentrations of the inflammatory cytokines TNF-α, IFN-γ, monocyte chemoattractant protein 1 (MCP-1), interferon-inducible cytokine IP-10 (IP-10), IL-22, interleukin 1 receptor type 1 (IL-1RA), IL18, IL-8, and macrophage inflammatory protein 1-alpha (MIP-1) 17 .

In a concept study, 13 severe COVID-19 patients requiring mechanical ventilation and receiving the standard care treatment were infused with adipose tissue-derived MSCs. Within 5 days of the treatment nine (70%) patients showed clinical improvements with significant reductions in CRP, lactate dehydrogenase (LDH), D-dimer, and ferritin. Moreover, five patients demonstrated improvements concerning B-lymphocyte alongside better CD4+ and CD8+ counts, and ultimately, after the MSCs infusion seven patients were extubated within a median time of 7 days 32 .

Shu, L. et al. conducted a single-center open-label, randomized trial involving 41 patients. Compared to the control group ( n = 29), CRP and IL-6 levels were significantly decreased from day 3 after UC-MSC infusions ( n = 12) 18 . In this study, the small sample size and the treatment change during the trial were the major limitations 18 .

Tang and colleagues tested the effects of infusions of menstrual blood-derived MSCs in two severe COVID-19 patients. They reported increased lymphocytes, decreased inflammation indicators (i.e., lower CRP and IL-6 levels) after MSC infusions, and antiviral treatment 36 .

Another pilot study conducted by Feng et al. investigated the efficacy of UC-MSCs in 16 patients; among them, seven were categorized as critically severe and nine as severe. They reported improvements in oxygenation index, CRP, and procalcitonin levels in severe and critically severe groups. In addition, the study noted augmented levels of CD4 + cells, CD8 + T cells, and NK cell counts within 28 days of the infusion 21 .

In a clinical trial involving MSC infusions in 31 patients, the PaO2/FiO2 level and lymphocyte counts showed a substantial increase, whereas the CRP, PCT, IL-6, and D-dimer were significantly decreased compared to the baseline values before infusions 11 .

In a single-center, open-label, non-randomized, noncontrolled conducted by Singh et al. in the earliest days of the COVID-19 outbreak, six patients received allogeneic cardiosphere-derived cells after receiving an anti-IL-6 agent. The levels of Ferritin, CRP, and IL-6 were decreased after the cardiosphere-derived cell infusion 22 . However, the decrease cannot be attributed only to cell therapy due to the prior treatment with anti-1L-6 agent 22 .

In a non-randomized open-label trial, Sengupta et al. apprised the safety and efficacy of an allogeneic bone marrow MSC-secreted extracellular vesicles (ExoFloTM) in 24 severe COVID-19 patients. Three days after infusions, they noted improvements in PaO2/FiO2 ratio ( p < 0.001), significant increases in the absolute counts of neutrophils, CD3+, CD4+, and CD8+ lymphocytes, and decline in CRP, ferritin, and D-dimer levels after 5 days of ExoFloTM treatment 29 . The major limitations of this study were the lack of randomization and blinding.

Chen et al. performing a single-center, open-label, non-randomized, noncontrolled trial comprising 25 patients, reported improved CT parameters in 16 patients after MSC infusions (64%). However, there were no changes in inflammation indices, including CRP, WBC, PCT, and IL-6 levels. Moreover, there were no changes in IgG or IgM. In contrast, the serum levels of lactate, cardiac troponin T, and creatine Kinase were elevated after the treatment 23 . Low statistical power due to the small sample size was a significant limitation in this study.

Häberle and associates, in a single-center, open-label, non-randomized, noncontrolled trial, enrolled 23 patients to either placebo ( n = 18) or MSC treatment ( n = 5). No differences in CRP and IL-6 were found between the groups. Notably, ferritin level was increased in the MSC-treated group after discharge. Notwithstanding, there was a significant reduction in neutrophils, lymphocytes, and leukocytes at discharge in the MSC treatment group compared to the placebo group 28 .

Evidence level 4C studies

Most studies with 4 C evidence levels were case reports, and hence the results could not be compared to findings seen in trials comprising larger cohorts of patients. It is also noteworthy that one cannot establish a cause–effect relationship from findings in case reports.

Adverse effects

All clinical studies analyzed the occurrence of adverse effects (AE) related to cell therapy. Studies whose primary endpoint was safety mainly defined the occurrence of prespecified infusion-associated AEs within 6 h of infusions in addition to cardiac arrest or death within 24 h of infusions. A total of 16 studies (55.1%) reported the occurrence of side effects, with only a minority of the studies (24.1%) attributing the side effects directly to the use of cell therapy. Approximately 41% of the studies reported that the observed side effects were not linked to the MSC treatment. Twenty-seven (93.1%) studies did not report the AEs during the administration of MSCs. The AE are also detailed in Table 4 .

AE related to cell infusion

As for the side effects observed at the time of infusions or within hours after infusions, one study reported hypoxemia, hypotension and/or hypertension, and muscle spasms, but they were easily controlled and did not acutely alter the patients’ medical conditions 16 . A clinical trial observed transient facial flushing and fever immediately after the infusion, which resolved spontaneously 17 . One clinical trial detected diarrhea and a rash in the chest area, but it resolved 31 . Another article reported a single Common Terminology Criteria for Adverse Events (CTCAE) grade-1 infusion-related reaction, which settled without intervention 33 . One patient experienced transient shivering, which occurred once in two cases and disappeared in less than 1 h 38 .

AE related to cell therapy

A study reported worsening of bradycardia in a subject who previously had bradycardia and required transient vasopressor treatment 14 . One pilot study observed liver dysfunction, heart failure, and allergic rash after treatment, but fortunately, all patients survived—the report did not specify the possible reason for the occurrence of these adverse reactions. Nevertheless, the serum levels of lactate, serum cardiac troponin, and creatine kinase were significantly increased after MSCs therapy, reinforcing the cautious use of MSC infusions in patients with previous metabolic acidosis and coronary heart disease 14 .

AE not related to cell therapy

Adverse events unrelated to cell therapy included progressively increased creatinine, epistaxis, and hematuria; a patient was also diagnosed with lower-extremity arterial thrombosis 16 . Another patient experienced hypoxemia, which was thought to be caused by the progression of COVID-19 based on previously existing symptoms 17 . One patient experienced pneumothorax, which recovered spontaneously under conservative treatment, and it was judged by the site investigators and found to be unrelated to MSCs intervention 19 . Feng et al. reported two patients with bacterial pneumonia and septic shock as complications of severe COVID-19 21 . In a case series, one patient developed nosocomial pneumonia with fever several days after MSC infusions, but it was not related to cell therapy as per the report. Nonetheless, it remains to be addressed whether MSC infusions increase the risk of infectious complications in COVID-19 patients with ARDS, although no such increases were seen earlier in MSC clinical trials involving immune-competent recipients 25 . Wilson et al. reported multiple embolic infarcts, which were thought to be present before MSC infusions based on a previous MRI scan 26 . Another trial observed a worsening hypoxic state, a respiratory failure requiring intubation, pulmonary embolism, and acute renal failure. The reactions were reviewed by an independent Data Safety Monitoring Board (DSMB), which concluded that the symptoms were unrelated to the therapeutic intervention 29 . One subject experienced pneumonia due to a methicillin-resistant Staphylococcus aureus, and another patient developed a fungal infection by Candida spp 32 .

There were no reported deaths directly linked to stem cell administration. Death was observed in 17 studies, and a total of 79 patients died out of 472, including placebo and patients who received MSCs. It was reported that 47 (14%) deaths occurred among 330 patients receiving MSC infusions, while the placebo groups had 32 (23%) deaths out of 142 patients. Five studies described deaths caused by complications of COVID-19 11 , 16 , 18 , 21 , 29 . One patient experienced repeated infections by multidrug-resistant pathogens and eventually suffered septic shock and died 13 . A phase II trial reported two deaths in the MSC-treated group, secondary to acute respiratory failure; both were reviewed and declared as unrelated to MSC infusions 14 .

Iglesias et al. reported two deaths; the first patient developed acute renal failure and the second cardiomyopathy and liver failure 16 . A pilot trial observed two deaths caused by pneumonia and septic shock, which were lethal complications of COVID-19 and occurred independently of MSC treatment 21 . A phase I trial noted one death in the MSC treatment group and two deaths in the placebo group, but none of the deaths were considered to be related to MSC infusions by the clinical investigators and were consistent with the patients existing disease processes 26 .

One patient had a fatal cardiopulmonary arrest; however, it was attributed to a preexisting history of coronary artery disease, and the DSMB judged that the death was likely not related to MSC infusions 27 . In another clinical trial, one patient in the MSC infusions group died of multiple organ failure, which was concluded as not related to MSC infusions by the clinical investigators and was consistent with the patient’s disease progression 31 . Jungebluth et al. reported multisystem organ failure after MSC infusions, possibly secondary to disseminated fungal infection and intra-abdominal sepsis 30 . Among the two patients who died, one was due to gastrointestinal bleeding and another to secondary pneumonia, unassociated with MSC therapy 32 . Another trial reported five deaths after cell infusions, two were intubated, two had signs of sepsis, the fifth patient had a cardiac arrest, and none of the deaths were considered connected to cell therapy 38 . The mortality after MSC infusions is described in Table 5 .

The present systematic review evaluated the available results of stem cell therapy for treating patients with COVID-19 and ARDS. By July 2021, according to the US National Institutes of Health (NIH) ClinicalTrials.gov database, 417 clinical investigations of cell therapies against SARS-CoV-2 have been conducted 39 . The database search for this systematic review was conducted in March 2021. Following the inclusion criteria evaluation, 29 articles were eventually included. The vast number of trials under progress shows that cell therapy has been suggested as a beneficial alternative to treating COVID-19 and its complications ARDS. Among the 417 registered trials, 203 were recruiting participants, five were enrolling participants by invitation, 32 were active, having already passed the recruitment phase, and 63 were completed. Of these 63, six trials already presented results. The remaining 114 trials were not in progress or had an unknown status. Novel therapies for COVID-19 are being explored with the primary objective of ameliorating the rates of morbidity and mortality by reducing lung injury, improving host immunity, and decreasing inflammation. Previous clinical trials have suggested that cell therapy is safe and leads to multiple beneficial effects in diverse respiratory conditions 40 , 41 , 42 , 43 , 44 , 45 . Our evaluation of the literature also suggested similar findings for cell-based therapy to treat patients affected by COVID-19 and ARDS.

In a recent report, Kim and Knoepfler evaluated stem cell (including MSCs) and NK cell therapy results from two clinical trial registries comprising 79 cell therapy trials for COVID-19. Among these, 67.1% were randomized, 25.3% were double-blinded, 34.2% were placebo-controlled, and only 22.8% met all three criteria, namely randomization, double-blinding, and placebo controls 46 . In the present systematic review, we included 29 published articles in which six (20.7%) were randomized, four (13.8%) were double-blinded, eight (27.6%) were placebo-controlled, and four (13.8%) met all three criteria. Overall, the results of cell therapy trials for COVID-19 have not reached a high impact, as trials meeting the three primary criteria, randomization, double-blinding, and placebo controls have been minimal.

MSCs are extensively used in cell therapy since their efficacy and safety have been shown in several diseases in preclinical and clinical trials, with significant efficacy in inflammatory and immunologic conditions 47 , 48 , 49 , 50 , 51 , 52 . Most of the cell therapy studies reviewed here utilized MSCs as donor cells in patients with COVID-19 and ARDS. The most common sources of MSCs used to treat respiratory pathologies are bone marrow, umbilical cord blood, adipose tissue, and endothelial progenitor cells 53 . MSCs are characterized by their immunomodulatory functions combined with their regenerative and proliferative ability to help severely affected COVID-19 patients. These cells secrete a variety of paracrine factors that may facilitate immunomodulation and anti-inflammatory effects, which have been hypothesized as possible mechanisms contributing to improved lung function and regeneration in respiratory diseases 54 , 55 . As seen in most of the analyzed studies, the beneficial effects of MSC intervention in COVID-19 and ARDS appeared to be linked to improvements in the host immune system and inflammatory response. Such a conclusion is based on increased lymphocyte counts and decreased CRP and pro-inflammatory cytokine levels, facilitating lung repair.

Regarding the clinical outcomes analyzed in this study, three outcome domains were identified, which were further subdivided into several parameters: immune response, pulmonary function, and systemic response. Although most cases of COVID-19 are mild to moderate in severity, ~15% of cases evolve to severe pneumonia, and ~5% progress to ARDS and multiple organ failure. The progression to a worse presentation is related chiefly to cytokine upregulation and exaggerated inflammatory response. In severe ailing patients, a hyperimmune reaction termed cytokine storm results in critical illness and end-organ dysfunction, with a high mortality rate 22 . Findings from the included articles indicate a possible positive impact of cell therapy on crucial immunological and inflammatory processes that lead to organ injury in SARS-CoV-2-infected patients. Laboratory measurements were common to 25 of the 29 included clinical articles, representing 86.2% of published reports. Among the clinical laboratory findings, 18 studies demonstrated improvements in immunomodulatory responses or inflammation markers. Therefore, reversing or even attenuating the cytokine storm appeared to be a lifesaver in patients with severe COVID-19 11 .

The primary site of SARS-CoV-2 infection is the respiratory system. The virus is responsible for injuring the lungs and causing impaired alveolar oxygenation, hypoxemia, and acidosis. Dysregulated pulmonary functions following SARS-CoV-2 infection should be considered, as it can progress to death or permanent lung injury if the patient recovers 56 . Therefore, notwithstanding the miscellaneous nature of measures exploited in different studies, 23 studies (79%) evaluated pulmonary functions. All these studies evaluated pulmonary functions using a variety of parameters, such as PaO2/FIO2, oxygen saturation ratio, lung imaging—chest CT or chest radiography, symptoms at admission and clinical status after cell therapy, discontinuation of oxygen support (intubation and ECMO) after cell infusion and reduction in mortality. In these studies, noteworthy improvements were reported between pre- and post-cell therapy status.

The studies categorized as evidence levels 1A and 1B reported that clinical outcomes could be influenced by cell preparation techniques leading to considerable differences in MSC viability 27 . Bellingan and colleagues also reported increased intensive care-free days, as well as a reduction in mortality 33 . Lanzoni and associates showed a considerable reduction in the concentration of pro-inflammatory factors. However, the small sample size and modified inclusion criteria during the trial are some of the limitations in these studies 14 .

Several studies with evidence level B demonstrated a decrease in pro-inflammatory biomarkers after cell therapy intervention 11 , 17 , 18 , 22 , 29 , 34 , 36 , 38 , improved lung function 34 , reduced B-lymphocyte counts 11 , 21 , 28 , 29 , 32 and better oxygenation levels 11 , 16 , 17 , 21 , 23 , 31 , 33 , 34 . However, these studies have significant limitations, including the lack of details on MSC origin or isolation 34 , the small sample size 18 , 21 , 32 , 38 , variability in MSC doses administered to patients 31 , 33 , irregular regimens of MSC administration 32 , insufficient cells for all the randomized patients assigned to receive cell infusions resulting in their assignment to the control group 18 , lack of a control group 11 , 21 , 23 , variability of treatments the patients received prior to cell infusions 22 , and the study design classified as retrospective 23 . Regarding 4 C evidence level studies, most of them were case reports, and hence, the extrapolation of these results to larger cohorts of patients will be difficult 24 .

Steroids act through similar proposed immune mechanisms as MSCs, the predominant cell type employed for infusions in the evaluated articles. Corticosteroid treatment for COVID-19 has proven to reduce mortality of patients on respiratory support 57 . However, some studies have discussed a few possible AE caused by the prolonged use of steroids, including hypertension, fluid retention, and increased risk of infection 58 . In addition, critically ill patients can have signs of hypercortisolism due to suppression of the neuroendocrine system, leading to the adrenal deficiency that could enhance mortality risk 59 , but it would differ based on individual variability in pharmacokinetics. The studies performing stem cell intervention reported restoration of lung function possibly through immunomodulation with just two transfusions, raising the debate that cell therapy could be beneficial in cases where patients do not respond well to standard treatment with steroids due to individual variability.

When proposing new therapeutic approaches, mortality is an important consideration, and this was one of the principal outcomes we reviewed in the present study. As per the reports, there were no deaths directly linked to cell therapy. Deaths were reported in 17 studies, and a total of 79 patients died. In all cases, it was suggested by the authors and committees that none were related to MSC infusions, but few studies were unsure about the cause of death. The studies also suggested that adverse events following MSC infusions in COVID-19 patients are rare or milder when present. The reported adverse events included facial flushing, transient fever, and hypoxia, but these were primarily attributed to the progression of COVID-19 and not directly to cell infusions 17 . Furthermore, cardiac arrest was reported 2 h after the infusion of the vehicle or cells in control and treated groups. These events were attributed to the infusion protocol (catheterization) rather than the MSC infusions per se 14 . Additionally, a study using MSCs for the treatment of ARDS reported a decrease in the mortality rate when patients received the therapy within 28 days. However, after 60 days, 38% of patients died. Still, the researchers concluded that the treatment was able to moderate the severe form of the disease and that the mortality in the treated group was not statistically higher than in the control group. They found that patients who received treatment with MSCs had numerically higher disease severity scores before the proposed treatment 27 . Besides, some of the collateral effects, including increased levels of lactate, serum cardiac troponin, and creatine kinase after MSC infusions, which resulted in liver dysfunction and heart failure, need to be investigated to determine their possible correlation with cell therapy and caution for patients with metabolic acidosis or coronary heart disease 23 . One study addressed the need for studies that correlate MSCs with an increased risk of infections; however, no such increase was reported in clinical trials 25 . All AE were controlled, indicating that cell therapy for treating COVID-19 and ARDS is likely safe.

Since the emergency pandemic situation broke out only recently, there was not enough time to produce a larger number of clinical trials with higher evidence levels, enrolling larger cohorts of patients and randomized controlled and multicenter studies involving cell-based therapy in severely affected COVID-19 patients. Randomized controlled trials have been pivotal to testing the safety and efficacy of a variety of interventions 60 . The novelty regarding the appraisal of safety and efficacy of stem cell infusions as an adjuvant treatment for COVID-19 is another critical issue that possibly explains the large number of low evidence studies discussed in this review.

In particular, we highlighted the efficacy of MSC therapy to halt the cytokine storm caused by SARS-CoV-2 infection, evident from the downregulated expression of pro-inflammatory cytokines and an increased concentration of an anti-inflammatory cytokine. Recently, COVID-19 was identified as a multi-organ infection with many symptoms linked to persistent manifestations and long-term effects on the cardiovascular and nervous systems after acute COVID-19 61 . In this context, MSC therapy could also help treat the long-term effects of COVID-19 infection, especially those emerging from chronic inflammation.

The number of patients recruited for the clinical studies was low since some trials were explored as a proof of concept and employed as compassionate use. Because the SARS-CoV-2 outbreak is still recent, there has not been enough time to produce extensive randomized clinical trials with a larger number of patients to understand better the effects of stem cell therapy on COVID-19-induced ARDS. Additionally, some of the analyzed studies are still in initial phases, and hence, our evaluation of findings was on the preliminary outcomes. Likewise, some studies did not use a control group, making the evaluation of the efficacy of MSC infusions difficult. Moreover, studies changed the course of treatment during the trial due to the lack of MSCs. Additionally, causes of death were unclear in some cases and were considered as unrelated to MSC infusions in others without adequate analysis and discussion on the issue. Therefore, additional clarifications are needed on how the cause of death was inferred as unrelated to cell infusions.

Furthermore, several aspects of cell therapy have not been satisfactorily elucidated. These include the best source of MSCs, the optimal dose of MSCs, the frequency of IV administration, and the therapeutic window for cell therapy intervention after COVID-19 infection to provide maximal protection to the lungs and other organs. It is also essential to consider that, according to Oxford and GRADE evaluation, most studies included here did not meet the highest level of evidence (A), and most of them were characterized as very low to moderate levels. Furthermore, it is too early to speculate on the exact mechanism by which stem cell therapy improves pulmonary complications, although this systematic review strived to provide provocative discussions.

Increased mortality worldwide due to SARS-CoV-2 infection and the emergence of new variants of the coronavirus emphasize the need to develop new therapeutic strategies for treating complications of COVID-19 and associated respiratory diseases such as ARDS. Treating COVID-19 complications is challenging since no treatment regimen has been entirely successful until now. Hence, identifying an effective and safe therapy for patients with severe COVID-19 is crucial for saving lives.

The use of cell therapy, especially MSCs, to treat COVID-19 appears promising based on the observations and findings in published studies. MSC therapy has shown promise to suppress cytokine storms, prevent the overactivation of the immune system, and repair the lung injury caused by SARS-CoV-2 infection. While the mechanisms of action of these cells are not yet fully understood, the beneficial effects promoted by MSCs are noteworthy. Thus, considering the current global pandemic situation, cell-based therapy could be considered an alternative treatment to containing the public health crisis, such as outbreaks in hospitals and care units and the collapse of medical infrastructure. Additionally, vaccines are already reducing the overall COVID-19 cases in many countries. However, cell-based therapy could also be used to treat the long-term sequelae caused by SARS-CoV-2 infection in patients, especially those related to chronic inflammation. For example, one in eight survivors of COVID-19 is diagnosed with neurological and psychiatric conditions, which may comprise confusion, problems in concentrating and memory recall, or depression. Nevertheless, more extensive double-blind, placebo-controlled, and multicenter clinical trials with a larger cohort of patients are necessary to validate the safety and efficacy of this therapeutic strategy.

This review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Statement 62 and was registered at the International Register of Prospective Systematic Reviews under identification number CRD42021248263.

Search strategy

A systematic search was conducted in MEDLINE (via PubMed), Embase, and Scopus. Comparable elements of research were used for all databases with some adaptations to each database search system. The descriptors comprised “COVID-19”, “SARS-CoV-2”, “Coronavirus”, “2019-nCoV”, “SARS”, “MERS”, “acute respiratory distress syndrome”, and “cell therapy.” Data were obtained from published articles from January 2000 to March 2021. There were no language restrictions.

Study selection

Three authors (L.L.L., L.P., and S.C.B.) independently assessed potentially eligible studies for their suitability for inclusion in this review. Disagreements were resolved by a fourth reviewer (GZ). During the screening of titles and abstracts, relevant papers were defined if they mentioned aspects of cell therapy applied as a therapeutic possibility for patients with COVID-19, ARDS, SARS, or MERS. Abstracts were analyzed according to the inclusion criteria, and all studies that met these criteria were included for full article reading.

Studies were included if they pertained to any stem cell therapy applied as a therapeutic alternative for patients with COVID-19, ARDS, SARS, or MERS with original data. The exclusion criteria were (1) review articles (including critical letters and systematic reviews), (2) studies with no mention of cell therapy, (3) studies relating to cell therapy applied to unspecified respiratory diseases, and (4) experimental studies. Figure 1 displays a flowchart of study selection and inclusion.

Data extraction

Regarding the appraisal of the data from all included studies, five tables were structured to summarize each study’s characteristics and findings, main parameters and outcomes, study design and classification of evidence, AE, and mortality. Table 1 shows clinical studies detailing the title, authors, investigated disease, donor cell type, route of cell administration, participant characteristics, n of the study, inclusion criteria, analyzed parameters, and primary outcomes. Table 2 summarizes the study design and classification of evidence from each study assessed using the Oxford Centre for Evidence-Based Medicine and the Grading of Recommendation Assessment Development and Education (GRADE) systems. Table 3 summarizes the key evaluated parameters separated into three domains: laboratory, pulmonary, and other parameters. Table 4 summarizes the AE encountered in different studies. Table 5 summarizes the mortality data described in different studies.

Data availability

The data are available from the corresponding author upon reasonable request.

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Acknowledgements

The authors are supported by Coordenação de Aperfeiçoamento de Pessoal de Nível Superior—Brazil (CAPES)—Finance Code 001; Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq). A.K.S. is supported by a grant from the National Institutes of Health Grant (R01NS106907-01).

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Gabriele Zanirati, Isadora Machado Ghilardi, Daniel Rodrigo Marinowic & Jaderson Costa Da Costa

School of Medicine, Pontifical Catholic University of Rio Grande do Sul (PUCRS), Porto Alegre, RS, Brazil

Laura Provenzi, Lucas Lobraico Libermann, Sabrina Comin Bizotto, Daniel Rodrigo Marinowic & Jaderson Costa Da Costa

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G.Z., designed the manuscript. G.Z., L.P., L.L.L., and S.C.B. performed the literature search and wrote the original draft. I.M.G., D.R.M., and A.K.S. critically revised the manuscript. J.C.C. designed, critically revised, and supervised the study. All authors approved the final version of the manuscript.

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Zanirati, G., Provenzi, L., Libermann, L.L. et al. Stem cell-based therapy for COVID-19 and ARDS: a systematic review. npj Regen Med 6 , 73 (2021). https://doi.org/10.1038/s41536-021-00181-9

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Bubble Boy, Berlin Patient and Butterfly Patient

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Three examples of stem cell therapies have made history: the cure of X-SCID-affected Jack Crick, the cure of the Berlin patient who, with the help of stem cells, escaped both HIV and leukemia and the rescue of the butterfly child Hassan, who was close to death before genetically modified stem cell therapy saved his life and gave him a future. Their cases, however, have remained highly regarded individual cases to this day. All patient stories are interesting against the background that they embody the future potential and the associated hope in stem cell therapy - but still represent the exceptional situation.

Patient Jack Crick

2004 Born in May 2004 X-SCID is diagnosed in September. The search for a suitable bone marrow donor unsuccessful. Gene therapy using the patient's own blood stem cells is successful, even without chemotherapy. 2011 Patient has had no symptoms since.

Attending Physician Bobby Gaspar, Great Osmond Street Hospital, London

SCID stands for severe combined immunodeficiency;

A weakening of the immune system due to the absence or lack of lymphocyte function; mutations in genetic information (DNA) cause the disruption of T cell development. The patients' immune systems cannot cope with the pathogens in our normal environment and the affected children must therefore live in a sterile environment.

Collection of hematopoietic stem cells (CD34-positive); inserting the corrected gene into the test tube using a retroviral vector (taken from the mouse leukemia virus); stem cells are returned to the patient.

Advantages: Use of own cells instead of foreign cells; low risk of rejection or incompatibility; no suitable donor necessary.

Discussion The introduction of a new gene can lead to changes in cell properties or to degeneration (cancer). Cases are known where patients developed leukemia. The trigger seems to be the retroviral vector. Research is being carried out on the use of newer HIV-derived lentiviral vectors, for example, which have a much better safety profile.

Search terms : Bubble Boy, David Vetter, Jameson Golliday

Patient Timothy Ray Brown

1966 Born in Seattle, USA 1995 Diagnosis: HIV positive until 2006 Treatment using highly active antiretroviral therapy (HAART): 600 mg Efavirenz, 200 mg Emtricitabine and 300 mg Tenofovir 2006 Diagnosis of acute myeloid leukemia (AML); chemotherapy treatment 2007 Treatment by allogeneic stem cell transplantation from a donor with a mutation in the CCR5 cell surface receptor. The mutation prevents the HI virus from penetrating the cells. since 2007 HI virus no longer detectable using common procedures 2008 Leukemia identified again; second stem cell transplantation (same donor) since 2008HI virus undetectable using common procedures; leukemia treatment successful; neurological disorders diagnosed

09/2020 Died of another attack of leukemia

HLA-type: B57

Attending Physician

Dr. Gero Hütter, Benjamin-Franklin-Klinikum Charité Berlin (bis 2009)

Bone marrow donor

HLA type: B57 Mutation: delta 32 on receptor CCR5

Transplantation of allogeneic stem cell transplantation of a donor with a mutation in the cell surface receptor CCR5. The mutation prevents the HI virus from entering the cells.

It is not clear whether this individual case is reproducible. The procedure is very expensive. In 2012, Steven Yukl (University of California, San Francisco) investigated nine billion patient blood cells using polymerase chain reaction (PCR). After several attempts he identifies fragments of the virus genome in the blood plasma. Douglas Richman (University of California, San Diego) also conducts blood tests and finds no residues. He considers contamination in the Yukl test possible; in addition, PCR is highly sensitive and error-prone.

Search terms: The Berlin Patient, Mississippi Baby, London Patient

Patient Hassan

Born in 2008 started treatment at the age of 7 2015: After fleeing from Syria to Germany, he suffered infections and chronic skin lesions as a result of the inherited disorder epidermolysis bullosa. 2015-2016: Skin graft involving 80 percent of the patient’s skin. Since then, the patient has been largely free of symptoms.

Attending Physician Tobias Rothoeft, Kinderklinik Bochum Tobias Hirsch, Universitätsklinikum Bergmannsheil (plastic surgeon) Michele De Luca, Center for Regenerative Medicine at the University of Modena (stem cell researcher)

Epidermolysis bullosa

Epidermolysis bullosa is an inherited disorder. Children with this condition are sometimes called butterfly children, because their skin is as fragile as a butterfly’s wings. This is because the upper layer of the skin (epidermis) is not properly attached to the layer underneath (dermis). People with this disease have a defective LAMB3 gene. This gene encodes the laminin-332 protein.

Skin cells from Hassan were sent to Italian experts in Modena for culturing. The scientists used retroviral vec�tors to insert a healthy LAMB3 gene into the skin cells. Retroviral vectors are viruses which have been specially modified to carry genes into cells. The genetically modified stem cells in the piece of skin were then cultured in a clean room laboratory to produce large pieces of skin suitable for grafting. Over a series of three operations in Germany, scientists then grafted the cultured tissue. In total, they replaced 80 percent of Hassan’s skin.

The new skin contains roughly the same amount of the laminin-332 anchor protein as normal, healthy skin.

There are around 35,000 children with epidermolysis bullosa in Europe. The severity of the disease varies great�ly. Until now, no treatment aimed at eliminating the underlying cause of the condition has been available. All gene therapies carry a risk that the new gene could be inserted into the wrong place in the genome, however. This can disrupt cell regulatory processes and cause cancer. The treatment Hassan underwent was risky and laborious. It was justified by the extent of his suffering and the fact that there was no prospect of his suffering being relieved by any other treatment.

Search terms: Patient Hassan, butterfly child

( https://www.spiegel.de/gesundheit/diagnose/gentherapie-junge-erhaelt-neue-haut-a-1177073.html )

Accompanying Material

Material: case studies, more content to the topic therapies.

Current status of stem cell therapies for various diseases, such as skin burns, liver failure, corneal clouding, leukemia, diabetes and Parkinson's disease

More teaching units

Basics Introduction and overview to stem cell research

Ethics Information and approaches for independent opinions on ethical aspects

Genetics Informations on (epi-)genetical changes in the genome

Clinical Trials

Stem cell therapy.

Displaying 75 studies

The purpose of this study is to assess the effectiveness and safety of Cx601, adult allogeneic expanded adipose-derived stem cells (eASC), for the treatment of complex perianal fistula(s) in patients with Crohn's disease over a period of 24 weeks and a follow-up period up to 52 weeks.

The purpose of this study is to evaluate the safety of using unlicensed cord blood units from the National Cord Blood Program in unrelated patients needing stem cell transplants, by carefully documenting all infusion-related problems.

The purpose of this study is to collect human menstrual blood at the time of gynecology visits in order to conduct future studies on the isolation and characterization of human menstrual blood and endometrial stem cells to better individualize treatment for abnormal uterine bleeding (AUB) and study the therapeutic properties of human menstrual-derived Mesenchymal Stem Cells (MSCs).

The purpose of this study is to collect fat and blood vessel wall tissue for processing into adult stem cells and then test those cells for specific biological markings.

The purpose of this study is to assess optimal dosing frequency, effectiveness and safety of adipose-derived autologous mesenchymal stem cells delivered into the spinal fluid of patients with multipe system atrophy (MSA).

Multiple system atrophy (MSA) is a rare, rapidly progressive, and invariably fatal neurological condition characterized by autonomic failure, parkinsonism, and/or ataxia. There is no available treatment to slow or halt disease progression.

The purpose of this study is to explore patients’ perceptions using educational interventions to debunk or prebunk misinformation of advertisements about unproven stem cell interventions (SCIs).

The purpose of this study is to assess the safety and tolerability of intravenously delivered mesenchymal steml cells (MSC) in one of two fixed dosing regimens at two time points in patients with chronic kidney disease.

The purpose of this study to test the feasibility and safety for autologous (from your own body) skin cells that are manufactured into stem cells of cardiac lineage to be delivered into the heart muscle to determine if those stem cells will strengthen the heart muscle and can be used as an additional treatment for the management of congenital heart disease.

The purpose of this study is to evaluate the long-term safety of a single dose of darvadstrocel in participants with Crohn's disease (CD) and complex perianal fistula by evaluation of adverse events (AEs), serious adverse events (SAEs), and adverse events of special interest (AESIs).

The purpose of this study is to assess the safety and feasibility of mesenchymal stem cells therapy in patients with advanced chronic obstructive pulmonary disease.

The aim of this study is to measure the differences in quality of life and mood of hematopoietic stem cell transplant (HCT) patients and their caregivers staying at a hospital hospitality house (HHH), such as the Gift of Life Transplant House, the Help in Healing Home, and the Gabriel House of Care versus staying at a hotel/rental apartment or house. The goal is to investigate if staying in a HHH, with its different environment and support systems and programs, has a positive impact on the quality of life (QOL) and mood of patients undergoing a HCT and their caregivers.

The purpose of this study is to evaluate the pharmacokinetics (PK), safety and tolerability of pegcetacoplan in patients with TA-TMA.

The purpose of this study is to produce, using current Good Manufacturing Practices (cGMPs), a bank of 50 primary fibroblast cell lines from skin biopsies obtained by consenting donors who meet 21 CFR 1271 donor eligibility criteria, and to use fibroblasts in the cell bank generated in aim 1 to produce new induced pluripotent stem cell lines using Good Manufacturing Practices (cGMPs). These iPSC lines will then be screened to identify those with optimal characteristics for treatment purposes, as well as for the potential generation of transplantable tissues and therapeutics for chronic disease.

The purpose of this study is to determine the safety and feasibility of allogeneic, culture-expanded BM-MSCs in subjects with painful facet joint arthropathy.

The purpose of this study is to determine determine the safety of intraspinal delivery of mesenchymal stem cells (MSCs) to the cerebral spinal fluid of patients with Amyotrophic Lateral Sclerosis (ALS) using a dose-escalation study.

This study aims to evaluate the safety of local delivery of AMSCs for recurrent GBM by noting the incidence of adverse events, as well as radiological and clinical progression.

To assess the preliminary efficacy of local delivery of AMSCs for recurrent GBM by comparing the clinical, survival, progression, and radiographic outcomes from patients enrolled in our study to historical controls from our institution.

To determine the safety and toxicity of intra-arterial infused autologous adipose derived mesenchymal stromal (stem) cells in patients with vascular occlusive disease of the kidney.

The purpose of this trial is to compare the treatment strategy of Autologous Hematopoietic Stem Cell Transplantation (AHSCT) to the treatment strategy of Best Available Therapy (BAT) for treatment-resistant relapsing multiple sclerosis (MS). Participants will be randomized at a 1 to 1 (1:1) ratio. All participants will be followed for 72 months after randomization (Day 0, Visit 0).

The purpose of this study is to evaluate the effectiveness of ibrutinib in reducing the incidence of NIH moderate/severe chronic GVHD.

The objective of this study is to evaluate the safety and feasibility of autologous mononuclear cells (MNC) collected from bone marrow (BM) delivered into the myocardium of the right ventricle of subjects with Ebstein anomaly undergoing surgical Ebstein repair. Additionally, the potential cardiovascular benefits will also be evaluated. This add-on procedure is anticipated to pose little risk to the subject and has the potential to foster a new strategy that leverages the regenerative capacity of individuals with congenital heart disease during the surgically mandated Ebstein repair.

The overall goal of this study is to determine the safety and feasibility of infusing adipose-derived mesenchymal stem cells directly into the artery of renal allografts with biopsy-proven rejection in order to reduce inflammation detected in the graft. We contend that future studies will show that administering immunomodulatory cells directly into the allograft will be more effective and safer than the current approaches of delivering massive doses of systemic immunosuppression.

Study participation involves receiving mesenchymal stem cells (MSC), created from the adipose tissue (body fat) of a donor, and infused into the main artery of a transplanted ...

The purpose of this study is to assess the safety of autologous mesenchymal stromal (stem) cell transfer using a biomatrix (the Gore Fistula Plug) to treat perianal fistula.

To assess the safety and feasibility of mesenchymal stem cells therapy in patients with transplant related bronchiolitis obliteran syndrome (BOS).

This phase I/II trial studies the side effects and best dose of oncolytic measles virus encoding thyroidal sodium iodide symporter (MV-NIS) infected mesenchymal stem cells and to see how well it works in treating patients with recurrent ovarian cancer. Mesenchymal stem cells may be able to carry tumor-killing substances directly to ovarian cancer cells.

The purpose of this study is to assess the safety and tolerability of intra-arterially delivered mesenchymal stem/stromal cells (MSC) to a single kidney in one of two fixed doses at two time points in patients with progressive diabetic kidney disease.

Diabetic kidney disease, also known as diabetic nephropathy, is the most common cause of chronic kidney disease and end-stage kidney failure requiring dialysis or kidney transplantation. Regenerative, cell-based therapy applying MSCs holds promise to delay the progression of kidney disease in individuals with diabetes mellitus. Our clinical trial will use MSCs processed from each study participant to test the ...

The purpose of the present study is to investigate the safety and efficacy of a single intrathecal injection of autologous, culture expanded AD-MSCs specifically in subjects with severe traumatic SCI when compared to patients undergoing physical therapy.

The purpose of this study is to collect, convert and bank blood cells from healthy volunteers into stem cells (iPSCs) at a current good manufacturing practice (cGMP) facility within the Discovery and Innovation building on the Mayo FLorida campus. After comprehensive validation, we will bank those cGMP-iPSCs as a resource available to Mayo Clinic investigators and also to outside investigators as appropriate. Those bio-specimens could be unique resources to develop new protocols for production of clinical grade iPSC-derived cells, cell-derived products such as extracellular vesicles, and tissues to support Investigational New Drug (IND) and related clinical trials.

To compare the effect of senolytic drugs on cellular senescence, physical ability or frailty, and adipose tissue-derived MSC functionality in patients with chronic kidney disease. Primary Objectives: To assess the efficacy of a single 3-day treatment regimen with dasatinib and quercetin (senolytic drugs) on clearing senescent adipose-derived MSC in patients with CKD. To assess the efficacy of a single 3-day treatment regimen with dasatinib and quercetin (senolytic drugs) on improving adipose-derived MSC functionality in patients with CKD. Secondary Objective: To assess the short-term effect of a single 3-day treatment regimen with dasatinib and quercetin (senolytic drugs) on ...

The investigators propose to study the safety of autologous mesenchymal stromal cell transfer using a biomatrix (the Gore Bio-A Fistula Plug) in a Phase I study using a single dose of 20 million cells. 20 patients (age 12 to 17 years) with Crohns perianal fistulas will be enrolled. Subjects will undergo standard adjuvant therapy including drainage of infection and placement of a draining seton. Six weeks post placement of the draining seton, the seton will be replaced with the MSC loaded Gore fistula plug as per current clinical practice. The subjects will be subsequently followed for fistula response and closure ...

The purpose of this study is to test the safety of this novel cell, combination- based regenerative therapy for use in patients with symptomatic focal cartilage defects of the knee.

This study aims to evaluate the safety of intramyocardial delivery of autologous umbilical cord blood-derived mononuclear cells during Fontan surgical palliation and measure surrogate markers of myocardial protection within a non-randomized study design to obtain prospective data from treatment and control populations.

The purpose of this study is to engage a cohort of patients who are avid information seekers about stem cells to assess their beliefs, online information sources and their credibility, and views on the credibility and persuasiveness of advertisements and warning messages available on the internet; we will use this data along with health behavior theories to develop communication messages aimed at inoculating patients against misinformation, correcting misconceptions, and providing evidence-based information about stem cell procedures.

Group 1: The primary purpose of this study is to evaluate the safety and tolerability of an autologous dendritic cells (DC) vaccine delivered by intra-tumoral injection in patients with primary liver cancer treated with high-dose conformal external beam radiotherapy (EBRT).

Group 2: The primary purpose of this study is to estimate the progression-free survival rate at 2 years post-registration to see if treatment is efficacious compared to historical data

The purpose of this study is to determine the safety and efficacy of intrathecal treatment delivered to the cerebrospinal fluid (CSF) of mesenchymal stem cells in ALS patients every 3 months for a total of 4 injections over 12 months. Mesenchymal stem cells (MSCs) are a type of stem cell that can be grown into a number of different kinds of cells. In this study, MSCs will be taken from the subject's body fat and grown. CSF is the fluid surrounding the spine. The use of mesenchymal stem cells is considered investigational, which means it has not been approved by ...

This study is an extension to re-treat partial and non-responders from the previously approved Phase 1 MCS-AFP protocols IRB #12-009716 (Crohn's Disease perianal fistulas) and 15-003200 (cryptoglandular perianal fistulas).

The investigators propose to study the safety of autologous mesenchymal stromal cell transfer using a biomatrix (the Gore® Bio-A®; Fistula Plug) in a Phase I study using a single dose of 20 million cells. Twenty adult patients (age 18 years or older) with refractory, complicated perianal fistulizing Crohn's disease will be enrolled. Subjects will undergo standard adjuvant therapy including drainage of infection and placement of a draining seton with continuation of pre-existing anti-Crohn's therapy. Six weeks post placement of the draining seton, the seton will be replaced with the MSC loaded Gore® Bio-A® fistula plug as per current clinical practice. ...

In this proposal, we will generate hiPSCs from AA patients and use our TREE-based approaches to introduce AA-associated variants into isogenic hiPSCs. In turn, we will use these isogenic hiPSC lines in a 3-D cortical model to address the following hypothesis-testing questions: (1) Does the presence of specific ABCA7 variants modulate disease-related phenotypes in a hiPSC-based system? (2) Are the risk modifying effects of the ABCA7 variants mediated through cell-autonomous or non-autonomous mechanisms? (3) Do these ABCA7 variants exert their effects through modulation of Aβ processing, secretion, and uptake? (4) What is the effect of these ABCA7 variants ...

The purpose of this study is to assess neurodevelopmental and psychosocial outcomes (i.e., executive function, social cognition, psychosocial adjustment, adaptive skills) in children with hypoplastic left heart syndrome (HLHS) who underwent right-ventricle-directed delivery of autologous umbilical cord derived mononuclear cells during staged cardiac surgical palliation, and to compare their outcomes to a matched sample of children with HLHS who did not receive autologous umbilical cord derived mononuclear cells during surgery.

The purpose of this study is to determine the safety and practical treatment use of STEM cells collected from a patient's own fat tissue, expanded in laboratory culture, and injected to treat symptoms of mild to severe knee osteoarthritis.

The purpose of this study is to assess the safety and effectiveness of a Stem cell transfer using a biomatrix (The Gore Fistula Plug) in patients with persistent symptoms of post-surgical gastrointestinal leaks despite current standard radiologic and endoscopic treatments. The subjects will be followed for fistula response and closure for 18 months. This is an autologous product (derived from the patient) and used only for the same patient.

The purpose of this study is to determine whether AVB-114 compared to standard of care treatment is effective in inducing remission of the treated complex perianal fistula in subjects with Crohn’s Disease. It also aims to assess clinical and radiologic components of fistula remission, safety of treatment, disease activity, patient Quality of Life, and patient care journey, between AVB-114 and standard of care treatment.

The purpose of this study is to assess the safety, tolerability, optimal dosing, effectiveness signals reflecting kidney repair, and markers of mesenchymal stem cells (MSC) function that relate to response to allogenenic adipose tissue-derived MSC in patients with Chronic Kidney Disease (CKD).

Will injection(s) of autologous culture-expanded AMSCs be safe and efficacious for treatment of painful Hip OA, and if so, which dosing regimen is most effective?

The purpose of this study is to determine the safety of using an autologous mesenchymal stromal cell (MSC) coated fistula plug in people with fistulizing Crohn's disease. Autologous means these cells to coat the plug come from the patient.

This study will evaluate the safety of intramuscular administration of PLX-R18 (allogenetic ex-vivo explanded placental adherent stromal cells) in subjects who have with incomplete hematopoietic recovery after hematopoietic stem cell transplantation.

The purpose of this study is to evaluate the safety and effectiveness of CD34+ cell intracoronary injections for treating coronary endothelial dysfunction (CED).

Ulcerative Colitis (UC) is a chronic inflammatory disease affecting the mucosal lining of the colon and rectum and the incidence is increasing, but the etiology remains unknown. Patients may require a proctocolectomy due to refractory disease. Prior to an operation, UC is treated with antibiotic therapy, immunomodulatory therapy and immunosuppressive agents. While there is an increasing number of approved biologics for the treatment of UC, there are many patients that still suffer from refractory disease. Thus, alternative mechanisms of therapy are desperately needed.

Treatments that have the potential to reduce mucosal inflammation could alleviate the pathology of luminal UC. This trial ...

The objective of this study is to generate a panel of iPSCs from 30 subjects who do not have a personal history of major neuropsychiatric disorders.

State-of-the-art induced pluripotent stem cells (iPSC) technology has become a powerful biomedical research tool and it clearly holds great potential for application to neuropsychiatric research.

The purpose of this study is to determine the success of mesenchymal stem cells, developed from the patient's own fat tissue, for reducing hemodialysis arteriovenous fistula failure when applied during the time of surgical creation.

The purpose of this study is to collect adipose tissue from patients undergoing elective surgery, or from healthy volunteers, test the donors to assure that they comply with all regulatory aspects required of healthy donors, expand and test mesenchymal stromal cells (MSC), and bank them for future use.

The current proposal aims to test the feasibility of immune function analysis for Tai Chi Easy (TCE) intervention in multiple myeloma (MM) patients undergoing autologous stem cell transplantation (ASCT) with concurrent exploration of health related quality of life (HRQOL).

The purpose of this study is to evaluate quality of life over time in patients treated with CAR-T therapy compared with autologous and allogeneic stem cell transplant.

This phase Ib/II trial studies how well dendritic cell therapy after cryosurgery in combination with pembrolizumab works in treating patients with stage III-IV melanoma that cannot be removed by surgery. Vaccines made from a person's white blood cells mixed with tumor proteins may help the body build an effective immune response to kill tumor cells. Cryosurgery, also known as cryoablation or cryotherapy, kills tumor cells by freezing them. Monoclonal antibodies, such as pembrolizumab, may block tumor growth in different ways by targeting certain cells. Giving dendritic cell therapy after cryosurgery in combination with pembrolizumab may work better in treating patients ...

The purpose of this study is to determine the effectiveness of MB-CART2019.1 cells administered following a conditioning lymphodepletion regimen in diffuse large B cell lymphoma (DLBCL) subjects who failed at least two lines of therapy as measured by objective response rate (ORR) at one month.

This is a double-blind, sham-controlled clinical study to evaluate the safety and feasibility of AMI MultiStem therapy in subjects who have had a heart attack (Non-ST elevation MI).

The purpose of this study is to evaluate safety, tolerability, pharmacokinetics, and effectiveness of SER-155 in adults undergoing hematopoietic stem cell transplantation to reduce the risk of infection and graft vs. host disease.

The purpose of this study is to compare the efficacy and safety of maribavir to valganciclovir for the treatment of cytomegalovirus (CMV) infection in asymptomatic hematopoietic stem cell transplant recipients.

The purpose of this study is to determine the safety of using an autologous mesenchymal stromal cell (MSC) coated fistula plug in people with rectovaginal fistulizing Crohn's disease. Autologous means that these cells that coat the plug come from you. You will be in this study for two years. There is potential to continue to monitor your progress with lifelong regular visits as part of your standard of care. All study visits take place at Mayo Clinic and Rochester, MN. The study visit schedule is as follows: Visit 1 (Week -6) - Screening visit: exam under anesthesia and surgery to ...

The purpose of this study is to evaluate the cellular composition of PRP produced by the Arthrex Angel System.

The purpose of this study is evaluate the safety of allogeneic adipose derived mesenchymal stem cell (AMSC) use during hemodialysis arteriovenous fistula and arterial bypass creation and its effectiveness on improving access maturation and primary anastomotic patency.

The purpose of this study is to evaluate the side effects of vaccine therapy in treating patients with glioblastoma that has come back. Vaccines made from a person's white blood cells mixed with tumor proteins from another person's glioblastoma tumors may help the body build an effective immune response to kill tumor cells. Giving vaccine therapy may work better in treating patients with glioblastoma.

The purpose of this trial is to evaluate the cosmetic role of novel anti-aging regenerative skin care product, human platelet extract (HPE), on skin rejuvenation.

Skin aging is a natural part of human aging process caused by intrinsic and extrinsic factors, such as genetics, cellular metabolism, chronic light exposure and other toxins. Cosmetological care for facial skin aging includes daily skin care, correct sun protection and aesthetic non-invasive procedures. 80 participants over the age of 40 years with moderate photoaging (dyschromic facial skin with fine lines and wrinkles) will be recruited from Mayo Clinic Center for Aesthetic Medicine and ...

The purpose of this study is to collect adiopose tissue to derive mesenchymal stem cells.

Although survivorship recommendations have been developed in areas such as lymphoma and stem cell transplant, the long-term effects of CAR-T therapy are unknown. In addition, relatively little is known about the psychosocial impact of CAR-T on survivors and their caregivers. Due to the intensive nature of CAR-T treatment and its unique side effects, including neurotoxicity in the acute setting and infections and financial burden in the long-term setting, a longitudinal study that assesses these issues in a quantitative and qualitative fashion is required. Consideration of both patient and caregiver needs is important for the provision of appropriate and ...

The study aims to characterize patient factors, such as pre-existing comorbidities, cancer type and treatment, and demographic factors, associated with short- and long-term outcomes of COVID-19, including severity and fatality, in cancer patients undergoing treatment. The study also is aimed to describe cancer treatment modifications made in response to COVID-19, including dose adjustments, changes in symptom management, or temporary or permanent cessation. Lastely, evaluate the association of COVID-19 with cancer outcomes in patient subgroups defined by clinico-pathologic characteristics.

The purpose of this study is to compare standard-dose combination chemotherapy to high-dose combination chemotherapy and stem cell transplant in treating patients with germ cell tumors that have returned after a period of improvement or did not respond to treatment. Drugs used in chemotherapy, such as paclitaxel, ifosfamide, cisplatin, carboplatin, and etoposide, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving chemotherapy before a stem cell transplant stops the growth of cancer cells by stopping them from dividing or killing them. Giving ...

The purpose of this study is to assess the feasibility and safety of delivering adipose mesenchymal stem cells (AMSCs) to kidney allografts.

The purpose of this study is to assess the safety, effectiveness, and overall benefit of FCR001 cell therapy in de novo living donor renal transplantation.

This randomized phase III trial studies rituximab after stem cell transplant and to see how well it works compared with rituximab alone in treating patients with in minimal residual disease-negative mantle cell lymphoma in first complete remission. Monoclonal antibodies, such as rituximab, may interfere with the ability of cancer cells to grow and spread. Giving chemotherapy before a stem cell transplant helps kill any cancer cells that are in the body and helps make room in the patient's bone marrow for new blood-forming cells (stem cells) to grow. After treatment, stem cells are collected from the patient's blood and stored. ...

The purpose of this research study is to evaluate a treatment regimen called IRD which will be given to participants after their stem cell transplant in an effort to help prolong the amount of time the participants are disease-free after transplant. IRD is a three-drug regimen consisting of ixazomib, lenalidomide (also called Revlimid), and dexamethasone. After 4 cycles of IRD, the participants will be randomized to receive maintenance therapy either with ixazomib or lenalidomide. 09/23/2019: Upon review of the interim analysis that suggested inferior progression-free survival in the ixazomib maintenance arm, there will be no further randomizations into the ...

The primary objective of the United States Food and Drug Administration (FDA) for this study is to demonstrate non-inferiority in subjects who received an allogeneic BMT for subjects randomized to Rezafungin for Injection compared to subjects randomized to the standard antimicrobial regimen (SAR) for fungal-free survival at Day 90 (±7 days).

The primary objective of the European Medicines Agency (EMA) for this study is to demonstrate superiority in subjects who received an allogeneic BMT randomized to Rezafungin for Injection compared to subjects randomized to the SAR for fungal-free survival at Day 90 (±7 days).

This randomized phase III trial studies ibrutinib to see how well it works compared to placebo when given before and after stem cell transplant in treating patients with diffuse large B-cell lymphoma that has returned after a period of improvement (relapsed) or does not respond to treatment (refractory). Before transplant, stem cells are taken from patients and stored. Patients then receive high doses of chemotherapy to kill cancer cells and make room for healthy cells. After treatment, the stem cells are then returned to the patient to replace the blood-forming cells that were destroyed by the chemotherapy. Ibrutinib is a ...

The primary purpose of this study is to identify the therapeutic effect of Adipose-Induced Regeneration (AIR) in radiation-induced skin injury of post-mastectomy breast cancer patients.

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Building More Homes for Hematopoietic Stem Cells

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A new study reveals how stem cell niche generation is regulated in bone marrow, which could lead to improvements in stem cell transplantation for the treatment of blood diseases.

Bone marrow transplants give patients new blood stem cells to replace original diseased cells and have helped millions of people with blood disorders, including cancer.

But for about one in every 10 patients, the introduced cells never take hold in the patient’s bone marrow, leaving patients open to severe infections and bleeding events that are often fatal.

By uncovering the mechanism that creates stem cell niches in bone marrow, the new study from Columbia Stem Cell Initiative researchers could lead to ways to increase the number of niches before transplantation and improve overall engraftment of transplanted cells.

“To improve engraftment, people have generally focused on improving the stem cells themselves, but these stem cells live in niches, specialized microenvironments in the bone marrow that nurture and protect the stem cells,” says Lei Ding, the Gurewitsch and Vidda Foundation Associate Professor of Microbiology & Immunology and Rehabilitation & Regenerative Medicine, who led the research.

“If we can create more niches, even without changing anything else, we should be able to increase the number of transplanted cells that engraft in the bone marrow and reduce graft failure.”

New niche generation requires m6a modifications

Little attention has been paid to how the niche is generated during development, because researchers had largely overlooked this process and considered the niche as a static, pre-existing structure.

To identify mechanisms that control niche development, Ding’s team examined gene activity of mouse bone marrow cells during and after the creation of niches to look for genes upregulated only during niche creation.

This analysis found that genes involved in mRNA processing and RNA methylation, particularly m6a modifications, were highly expressed during niche creation but not after.

That led the researchers to the Mettl3 gene, which is responsible for adding m6a modifications to mRNA, and the discovery that Mettl3 activity is needed to generate stem cell niches. Without Mettl3, Ding’s team found, niche generation was compromised in both number and quality, more bone cells were generated, and fewer hematopoietic stem cells took up residence in the bone marrow.

The researchers also identified a target of Mettl3—Klf2—which must be suppressed by m6a modifications during niche development.

“This study is important because it reveals the first specific mechanism of niche creation,” Ding says, “and shows us that niche creation is controlled genetically.”

“We are super excited about the possibility to create more niches by modulating gene function,” says first author Longfei Gao, a postdoctoral fellow in Ding’s lab.

Artificial niches

The next step for the researchers is to see if they can increase niche generation in adult mice.

“At this stage we’re still doing a lot of genetics to find a driver that can boost niche creation, so we don’t yet have a way to translate our finding to patients,” Ding says.

The findings may also be an important step toward the creation of niche organoids in the laboratory.

“Right now, we can’t culture niche cells very well,” Ding says. “If we can create a niche in the lab, we can better understand how the niche supports stem cells and maybe use such systems to generate more stem cells for patient transplants.”

Top image shows normal hematopoietic stem cell niches (pink) in the bone marrow of a mouse. Image provided by Lei Ding.

The research was supported by the National Institutes of Health (grants R01HL153487, R01HL155868, R01GM146061, and P30CA013696), a NYSTEM training grant, an American Heart Association postdoctoral fellowship, a Rita Allen Foundation Scholar Award, a Scholar Award from the Leukemia and Lymphoma Society, and an Irma Hirschl Research Award.

All authors (from Columbia): Longfei Gao, Heather Lee, Joshua H. Goodman, and Lei Ding.

The authors declare no competing interests.

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Case Studies

Mesenchymal stem cells heal a large foot ulcer resulting from a 30,000 volt electrocution, contact our experts and start feeling better.

Open access
Published: 12 May 2024

Multipotent/pluripotent stem cell populations in stromal tissues and peripheral blood: exploring diversity, potential, and therapeutic applications

Domenico Aprile 1 ,
Deanira Patrone 1 ,
Gianfranco Peluso 2 &
Umberto Galderisi ORCID: orcid.org/0000-0003-0909-7403 1 , 3 , 4

Stem Cell Research & Therapy volume 15 , Article number: 139 ( 2024 ) Cite this article

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The concept of “stemness” incorporates the molecular mechanisms that regulate the unlimited self-regenerative potential typical of undifferentiated primitive cells. These cells possess the unique ability to navigate the cell cycle, transitioning in and out of the quiescent G0 phase, and hold the capacity to generate diverse cell phenotypes. Stem cells, as undifferentiated precursors endow with extraordinary regenerative capabilities, exhibit a heterogeneous and tissue-specific distribution throughout the human body. The identification and characterization of distinct stem cell populations across various tissues have revolutionized our understanding of tissue homeostasis and regeneration. From the hematopoietic to the nervous and musculoskeletal systems, the presence of tissue-specific stem cells underlines the complex adaptability of multicellular organisms. Recent investigations have revealed a diverse cohort of non-hematopoietic stem cells (non-HSC), primarily within bone marrow and other stromal tissue, alongside established hematopoietic stem cells (HSC). Among these non-HSC, a rare subset exhibits pluripotent characteristics. In vitro and in vivo studies have demonstrated the remarkable differentiation potential of these putative stem cells, known by various names including multipotent adult progenitor cells (MAPC), marrow-isolated adult multilineage inducible cells (MIAMI), small blood stem cells (SBSC), very small embryonic-like stem cells (VSELs), and multilineage differentiating stress enduring cells (MUSE). The diverse nomenclatures assigned to these primitive stem cell populations may arise from different origins or varied experimental methodologies. This review aims to present a comprehensive comparison of various subpopulations of multipotent/pluripotent stem cells derived from stromal tissues. By analysing isolation techniques and surface marker expression associated with these populations, we aim to delineate the similarities and distinctions among stromal tissue-derived stem cells. Understanding the nuances of these tissue-specific stem cells is critical for unlocking their therapeutic potential and advancing regenerative medicine. The future of stem cells research should prioritize the standardization of methodologies and collaborative investigations in shared laboratory environments. This approach could mitigate variability in research outcomes and foster scientific partnerships to fully exploit the therapeutic potential of pluripotent stem cells.

The term “stemness” refers to the molecular unlimited self-regenerative process, triggered by undifferentiated primitive cells that have the ability to enter and exit the G0 phase of the cell cycle and the power to generate one or more cell phenotypes. Stem cells, undifferentiated progenitors endowed with remarkable regenerative potential, display a diverse and tissue-specific distribution throughout the human body. The identification and characterization of distinct stem cell populations across various tissues have transformed our comprehension of tissue homeostasis and regeneration [ 1 ]. From the hematopoietic system to the nervous and musculoskeletal systems, the presence of tissue-specific stem cells underscores the complexity and adaptability of multicellular organisms. Notably, accumulating evidence emphasizes that different tissues harbor unique types of stem cells, each equipped with specialized functions tailored to the specific microenvironment of their residing niche. Understanding the intricate traits of tissue-specific stem cells is vital for propelling regenerative medicine forward and unlocking their full therapeutic capabilities [ 2 ].

Stem cells are characterized by their unique ability to undergo continuous division (self-renewal) and, upon specific cues, differentiate into various specialized cell types [ 3 ]. Classification of stem cells is based on their differentiation potential, encompassing totipotent and pluripotent stem cells associated with early embryo development, as well as multipotent, oligopotent, and unipotent stem cells prevalent in adult tissues, each displaying varying degrees of differentiation capacity. Totipotent cells are present in the earliest developmental stages, whereas pluripotent cells are located in the inner cell mass of the blastocyst, capable of giving rise to a diverse array of cell types representing the three germ layers but not extraembryonic tissues. Multipotent stem cells, such as mesenchymal and hematopoietic stem cells, can differentiate into various cell types within the same embryonic germ layer. Oligopotent and unipotent stem cells, often referred to as progenitor cells, have limited differentiation potential [ 4 ].

The classification of stem cells based on their potency often arises from in vitro experiments demonstrating their differentiation potential. However, for some stem cells, the in vitro differentiation potential may not accurately reflect their in vivo differentiation capacities. Mesenchymal stromal cells (MSCs) encompass a stem cell population capable of in vivo differentiation into mesodermal derivatives, such as osteocytes, adipocytes, and chondrocytes. Nevertheless, certain in vitro studies have indicated that these cells may also differentiate into neurons and other ectodermal and/or endodermal cell phenotypes.

Discrepancies between in vitro and in vivo physiological differentiation potential, along with variations in in vitro properties depending on isolation and cultivation procedures, may lead to the misclassification of stem cells [ 5 ]. In this scenario, it is important to emphasize that the in vitro biological properties of stem cells may not necessarily reflect their physiological functions in the body. The classification of stem cells for investigations aimed at isolating and cultivating stem cells for therapeutic purposes must not be confused with studies devoted to dissecting the physiological role of stem cells in tissue renewal and organismal homeostasis.

Recent discoveries suggest the existence of a diverse group of non-hematopoietic stem cells (non-HSC) primarily within bone marrow stromal tissue, as well as in the stromal components of other tissues, alongside well-established hematopoietic stem cells (HSC). Moreover, it has been theorized that among these non-HSC, a particularly rare subset exhibits several characteristics of pluripotent stem cells (PSC). In vitro studies have demonstrated the capacity of these potential PSC to differentiate into cells representing all three germ layers, and they have been identified in the scientific literature under various names, including i) multipotent adult progenitor cells (MAPC), ii) marrow-isolated adult multilineage inducible (MIAMI) cells, iii) small blood stem cell (SBSC), iv) very small embryonic-like stem cells (VSELs), and v) Multilineage differentiating stress enduring (MUSE) cells. The assignment of different nomenclatures to similar or overlapping populations of primitive stem cells within the BM may stem from diverse experimental approaches [ 3 , 4 , 5 , 6 ].

This review aims to provide a comprehensive report and comparison of various subpopulations of multipotent/pluripotent stem cells derived from stromal tissues. Through an analysis of the isolation methods and surface marker expression associated with these diverse populations, the goal is to develop a thorough understanding of the commonalities and differences among stem cells found in stromal tissues. This is to ascertain whether stem cells isolated using different methods and subsequently labeled with distinct names may refer to a singular core population of stem cells. In this scenario, the diverse biological properties of the various non-HSC stem cells may depend on the percentage of stem cells and progenitors present in the samples isolated using different procedures. It should be noted that even stem cells isolated at the 'purest' grade contain several subpopulations, including both stem cells and lineage-committed cells at various degrees of maturation [ 7 , 8 ].

Stromal cell population

The term “stromal cells” encompasses a diverse group of connective tissue cells forming the structural framework for organs and playing crucial roles in health and disease. Coexisting with parenchymal cells that define organ-specific functions, stromal cell populations include fibroblasts, pericytes, and telocytes found across various organ systems, alongside with heterogenous cell populations such as bone-marrow-derived mesenchymal stem/stromal cells (MSCs) and adipose tissue-derived stem/stromal cells (ASCs), which contain stem cells, progenitor cells and other stromal cell types [ 9 , 10 , 11 ]. Recent research has unveiled the molecular underpinnings of stromal cell contributions to processes such as tissue development, homeostasis, regeneration, immune responses, cancer, and disease [ 12 ]. While stromal cells shape their microenvironment, their functions are profoundly influenced by tissue context.

The intricate landscape of stromal cells unveils a diverse array of subpopulations, including MUSE cells, MIAMI cells, MAPCs and VSELs, each holding unique characteristics within the realm of adult multipotent/pluripotent stem cells. These distinct entities, nestled within the stromal tissues, add a layer of complexity to our understanding of the physiological regenerative potential of our tissues and organs [ 13 ]. The recognition and exploration of these specific multipotent/pluripotent subpopulations within stromal tissues broaden the horizons of regenerative medicine, offering promising avenues for therapeutic applications. Harnessing the regenerative capabilities of MUSE cells, MIAMI cells, MAPCs and VSELs, from stromal environments could pave the way for innovative approaches in tissue repair and disease treatment, elevating the role of stromal cells as crucial players in the pursuit of regenerative medicine breakthroughs.

Multilineage-differentiating stress enduring (MUSE) cells

In 2010, Professor Dezawa's research group at the University of Sendai, Japan, successfully isolated a distinctive stem cell population termed Multilineage-differentiating Stress Enduring cells (MUSE) from the mononuclear cell fraction of the bone marrow [ 14 ]. These endogenous, stress-resistant stem cells express pluripotency master genes and feature specific surface markers like SSEA-3 [ 15 , 16 ]. The utilization of FACS and MACS in isolation protocols ensures the dependable purification of MUSE cells.

MUSE cells were initially identified in humans and mice, and subsequently in other species, including rat, rabbit, sheep, and monkey, demonstrating evolutionary conservation and broad applicability [ 17 , 18 ]. These cells are found in various tissues, such as fibroblasts, adipose tissue and bone marrow MSCs, and peripheral blood, showcasing their versatile accessibility for therapeutic purposes [ 19 ].

In vitro, MUSE cells exhibit extensive trilineage differentiation into hepatocytes, neural/neuronal-lineage cells, cardiomyocytes, skeletal muscle, and glomerular cells, highlighting their pluripotent nature. Their distinctive ability for clonal in vitro trilineage differentiation, as confirmed by RT-qPCR and ICC analyses, underscores their unique pluripotent characteristics, crucial for controlled and specific differentiation in therapeutic applications. In vivo, MUSE cells differentiate into diverse cell types, emphasizing their potential in regenerative medicine.

MUSE cells, present in connective tissues, remain quiescent but activate under stress conditions [ 20 ]. Their homing ability to damaged tissues and resistance to stressors like H 2 O 2 and UV make them advantageous for therapeutic applications [ 21 ]. MUSE cells grow as single cells in suspension and form clusters positive for both MSC marker CD105 and SSEA-3. Upon transfer to an adhesion system, single cells express markers of mesoderm, ectoderm, and endoderm, indicating trilinear differentiation and self-renewal ability through multiple culture cycles (Table 1 , Fig. 1 ).

Key Properties of Stromal and Peripheral Blood Stem Cell Populations (MUSE, VSEL, SSBC, MIAMI, MAPC). Localization, surface markers, isolation methods, and main properties of stem cells have been reported

Comprehensive analyses of MUSE cells have included investigations into their transcriptomics and proteomics, identifying specific factors within the secretome that significantly contribute to stress resistance and tissue repair mechanisms [ 22 ]. The secretome of MUSE cells reveals a unique protein profile, including Serpins and 14-3-3 proteins, which contribute to stress tolerance and apoptosis inhibition [ 23 ]. Notably, in severe tissue damage, MUSE cells migrate from the bone marrow to peripheral blood, guided by the sphingosine-1-phosphate (S1P) pathway, particularly the S1PR2 receptor. In injured areas, MUSE cells persist and phagocyte apoptotic differentiated cells using distinct phagocytic receptor subsets compared to macrophages. The phagocyted contents from the differentiated cells, such as transcription factors, were promptly discharged into the cytoplasm, moved into the nucleus, and attached to the promoter regions of the stem cell genomes. Within 2 days, the MUSE cells exhibited lineage-specific markers associated with the phagocyted differentiated cells [ 21 , 24 ]. MUSE cells exhibit immunomodulatory capacity, activating regulatory T cells, suppressing dendritic cell differentiation, and expressing HLA-G, suggesting potential in immune tolerance [ 25 ].

MUSE cells possess significant regenerative potential, demonstrated by their safety, accessibility, in vivo differentiation, and therapeutic effects in various models, including lacunar infarction, acute myocardial infarction, amyotrophic lateral sclerosis, and liver fibrosis [ 26 , 27 , 28 , 29 , 30 , 31 ]. Clinical trials for conditions like acute myocardial infarction, ischemic stroke, epidermolysis bullosa, spinal cord injuries, ALS, cerebral palsy, and COVID-19-related acute respiratory distress syndrome are underway in Japan. The absence of tumorigenesis post-injection and their applicability without gene manipulation or cytokine treatment further underscore MUSE cells' promise in regenerative medicine.

In summary, MUSE cells present a unique pluripotent profile, making them versatile candidates for regenerative medicine with applications in diverse biological contexts.

Very small embryonic-like (VSEL) stem cells

Discovered in 2006, Very Small Embryonic-Like (VSEL) stem cells have emerged as a unique subset within the realm of stem cell research, holding great promise for regenerative medicine [ 32 ]. Unlike conventional stem cell populations, VSEL cells present distinct characteristics that set them apart and offer an ethical alternative to embryonic stem cells. VSEL cells, remarkably small in size (3–6 μm), lack certain lineage markers (CD45–, lin–), and express specific surface antigens like Sca-1 and CXCR4. They also exhibit pluripotency markers, including Oct-4, SSEA-3, Nanog, and Rex1, commonly associated with embryonic stem cells [ 33 ]. VSELs have been identified in both mice and humans, displaying remarkable differentiation potential and widespread localization in tissues such as bone marrow, umbilical cord blood, and peripheral blood. The sorting method involves the use of beads of predefined sizes, isolating Oct-4 + CXCR4 + SSEA-1 + Sca-1 + CD45 – lin – cells in mice and Oct-4 + CXCR4 + SSEA-4 + CD133 + CD45 – lin – cells in humans [ 34 , 35 ]. These sorted cells display large nuclei with unorganized chromatin (euchroma). Approximately 5–10% of isolated VSELs, when cultured, can form VSEL-Derived Sphere (DS), resembling embryoid bodies. These structures, observed in young mice, exhibit features such as immature cells with large nuclei, and express pluripotency markers. VSEL-DS, when replated, can generate new secondary or tertiary spheres and, under conducive conditions, differentiate into various cell types [ 36 , 37 ]. These cells exhibit not only in vitro trilineage differentiation but also contribute to diverse in vivo outcomes, including the development of bone-like structures, endothelial cells, cardiomyocytes, hepatocytes, and pancreatic cells. VSELs demonstrate migratory capabilities, responding to specific tissues during migration assays and showing a prompt response to tissue damage. Moreover, they exhibit stress resistance, surviving high doses of gamma-irradiation and extrinsic heat stress, showcasing their robust nature in adverse conditions (Table 1 , Fig. 1 ).

Comprehensive analyses have been conducted on the proteome and transcriptome of VSELs, revealing dynamic profiles that contribute to their functional diversity. Researchers have diligently investigated the molecular characteristics of VSELs to understand their developmental origin. By studying highly purified double-sorted VSELs from murine bone marrow under steady-state conditions, it has been observed that these cells express genes associated with both epiblast specification (e.g., Stella, Prdm14, Fragilis, Blimp1, Nanos3, and Dnd1) and primordial germ cells (PGCs). Notably, PGC-specific genes like Dppa2, Dppa4, and Mvh, which are characteristic of late-migratory PGCs, were also expressed. Authors hypothesized that VSELs maintain quiescence in adult tissues through mechanisms similar to those governing PGC quiescence, involving epigenetic modifications of paternally imprinted genes [ 38 ]. These findings suggest that VSELs modify the imprinting of early-development imprinted gene loci (e.g., Igf2–H19), rendering them resistant to insulin-like growth factor signaling. These insights strengthen the link between PGCs and VSELs as potential precursors for long-term tissue regeneration.

Some studies suggest that VSELs may possess immunomodulatory capabilities, indicating their potential interactions with the immune system. Claims have been made that VSELs could regulate the immune response, potentially enhancing it in cases of infections or injuries and attenuating it in conditions of autoimmune hyperactivity. However, these findings have been reported primarily on the websites of private regenerative medicine centers, lacking validation through scientific evidence.

On the other hand, several clinical trials suggest that VSELs might exhibit immune-privileged properties, potentially enabling transplantation across histocompatibility barriers without triggering an immune response. Nevertheless, further research is necessary to comprehensively understand the underlying mechanisms and to develop effective therapies utilizing VSELs [ 39 ].

VSELs are currently being investigated in clinical trials for various applications [ 40 , 41 ]. In the context of knee osteoarthritis, researchers are exploring the safety and efficacy of autologous VSELs by injecting them into the affected knee. Additionally, VSELs are being evaluated for facial skin antiaging, where they are injected into specific areas. Furthermore, these stem cells are being studied for their potential role in addressing organic erectile dysfunction. Overall, VSELs hold promise as a fascinating avenue for tissue regeneration and aging-related therapies.

A significant application of VSEL cells has been explored in diabetes repair. VSELs, isolated from mouse bone marrow, were analyzed for specific markers and demonstrated the ability to differentiate into various cell types. Upon intravenous injection into mice with pancreas damage, VSELs migrated to the pancreas, survived, and resulted in a significant decrease in blood glucose levels for at least two months. The mice also experienced gradual weight gain [ 42 ]. This groundbreaking research suggests that VSELs could be a promising strategy for treating diabetes and other regenerative diseases, offering a viable alternative to traditional stem cell therapies [ 35 , 43 ].

In summary, VSELs present a unique combination of migratory, stress-resistant, and differentiation features, positioning them as resilient contributors to tissue regeneration and repair. This makes them promising candidates for therapeutic applications in regenerative medicine, akin to MUSE cells, showcasing distinct characteristics in diverse biological contexts.

Marrow isolated adult multilineage inducible (MIAMI) cells

Marrow Isolated Adult Multilineage Inducible (MIAMI) cells were discovered in 2004 by Gianluca D'Ippolito and his team [ 47 ]. These cells have sparked significant interest in the field of regenerative medicine due to their distinctive characteristics and promising therapeutic potential. The process of isolating MIAMI cells involves a specialized expansion and selection procedure that emulates the in vivo microenvironment of primitive stem cells in the bone marrow. This process entails co-culturing adherent and non-adherent marrow cells on fibronectin under low oxygen conditions (3%) [ 48 ]. Compared to human mesenchymal stem cells, which exhibit a typical fibroblastic morphology with few long and thin cellular processes, MIAMI cells appear smaller, with a more compact and rounded cytoplasm. The remarkable ability of MIAMI cells to differentiate into various lineages—mesodermal, ectodermal, and endodermal—makes them versatile for addressing diverse tissue regeneration needs. Surface marker analysis plays a key role in identifying and characterizing these cells. They express specific markers such as CD29, CD63, CD81, CD122, CD164, cMet, BMPR1B, and NTRK3, while significantly lacking expression of markers like CD34, CD36, CD45, cKit, and HLA-DR. This distinctive marker profile contributes to their unique identity. Additionally, MIAMI cells express typical embryonic stem cell markers such as Sox2, Nanog, Oct-4, and Rex-1, along with strong telomerase expression, indicating their pluripotent characteristics, despite exhibiting a rounded and compact morphology with a high nucleus-to-cytoplasm ratio [ 47 ]. MIAMI cells isolated from various donors' bone marrow show consistently similar genetic expression, regardless of age and sex, and appear to share more proteins with human embryonic stem cells than with mesenchymal stem cells, but without the potential to form teratomas, as they have been demonstrated to be non-cancerogenic [ 48 ]. Additionally, the expression level of distinctive markers of MIAMI cells remains constant regardless of age and gender. Furthermore, although the proportion of MIAMI cells compared to the total marrow nucleated cells decreases from 0.01% at the age of 3 to 0.0018% at the age of 45, their overall number remains stable after the age of 45.

Due to these characteristics, MIAMI cells are currently under investigation in various clinical applications, including tissue regeneration [ 49 ]. MIAMI cells express numerous markers similar to embryonic stem cells, they do not possess complete self-renewal capacity; however, they appear to respond to specific molecular signals in the right environmental conditions to induce self-renewal. This can be exploited to manipulate these cells to become more stable, maintain their pluripotency, and support their immunoregulatory properties for longer periods. Importantly, MIAMI cells show rapid proliferation without signs of senescence, ensuring the maintenance of their differentiation potential during prolonged culture periods, which is crucial for scalability and potential clinical applications. MIAMI cells demonstrate migratory capabilities to damaged tissues and immunomodulatory capacity, suggesting their potential in tissue repair and immunomodulation [ 50 , 51 ]. In therapeutic applications, MIAMI cells have shown promise in various pathologies, such as in the treatment of peripheral vascular disease (PVD). Studies using a murine model of critical limb ischemia have demonstrated that the combination of MIAMI cells with a bilayer electrospun gelatin B nanofiber construct (BIC) significantly improved limb recovery compared to single treatments [ 52 ]. This combined approach led to improved blood flow restoration, reduced ischemia and necrosis, and prevention of intermuscular adipose tissue infiltration (IMAT). However, further research and clinical studies are essential to unveil the full therapeutic potential of MIAMI cells and establish their role in treating a variety of diseases and conditions.

Multipotent adult progenitor cells (MAPCs)

The multipotent adult progenitor cells (MAPCs) were first identified in human bone marrow and subsequently confirmed in animal models, such as mice and rats. MAPCs have demonstrated a remarkable ability to differentiate into a variety of cell lineages, including mesodermal, ectodermal, and endodermal lineages. These cells can be isolated from various tissue sources, including bone marrow, brain, muscle and bone tissue [ 53 , 54 ]. However, isolating MAPCs from bone marrow has been one of the most common and widely studied methods to date. The process of isolating MAPCs from bone marrow involves several key steps that have been developed and optimized over the years. One distinctive feature of this process is the use of low-oxygen conditions, typically around 5%, during cell isolation. This hypoxic environment mimics the physiological conditions present in the bone marrow and promotes the maintenance of the unique properties of MAPCs. Once a critical mass of cells is reached in culture, MAPCs can then be selected using specific cell surface markers through flow cytometry techniques, allowing for the separation of MAPCs based on their expression of specific markers such as CD44, CD13, CD73, CD90, CD105, CD31, and CD49d [ 53 ]. Despite MAPCs may be present in a population of MSCs, the crucial points that define MAPCs compared to MSCs essentially lie in their different origins, not only mesodermal, and surface marker expressions. These differences define distinct potentials, such as a broader differentiative capacity, a more pronounced immunomodulatory capacity, and better performance in cell therapy. One of the most remarkable features of MAPCs is their ability to surpass the differentiation potential of traditional MSCs, which are also frequently used in the field of regenerative medicine. Therefore, not only do they possess the ability to differentiate into a variety of cell types, like MSCs, but they also exhibit exceptional plasticity and adaptability, allowing them to cross lineage barriers more completely and efficiently. MAPCs demonstrate immunomodulatory properties that go beyond those of MSCs. They can modulate immune responses, playing a role in regulating inflammation and promoting a favorable environment for tissue healing. This immunomodulatory behavior of MAPCs makes them particularly interesting for application as universal donors, as they can be transplanted into patients without the risk of immunological rejection. The option to use MAPCs as universal donors is highly appealing in regenerative medicine, as it reduces the need to find a matching donor and the risk of tissue compatibility complications. The clinical applications of multipotent adult progenitor cells (MAPCs) are extremely broad and promising, with various pieces of evidence confirming their efficacy in crucial therapeutic contexts. One of the most interesting aspects is the use of MAPC secretome, known as MAPC-conditioned medium (MAPC-CM), as a therapeutic agent for wound healing. This secretome contains a rich mixture of growth factors, cytokines, and other bioactive molecules that influence a series of key processes in tissue repair. Studies conducted on animal models with excisional wounds have shown that the application of MAPC-CM can promote cell migration, stimulate cell proliferation, promote collagen deposition, and enhance the formation of new blood vessels, known as angiogenesis. These combined effects contribute to the rapid and effective healing of damaged tissues. Furthermore, clinical studies have demonstrated that MAPCs can have a significant impact on reducing myocardial scars in patients who have suffered from a myocardial infarction [ 55 ]. This is particularly relevant considering that myocardial scars can compromise long-term cardiac function and increase the risk of cardiovascular complications. MAPCs, due to their ability to differentiate into cardiac cells and their modulating effect on the surrounding microenvironment, can contribute to the regeneration of damaged cardiac tissue and the reduction of scars, thereby improving cardiac function and reducing the risk of complications. In the context of stroke recovery, the MASTERS study has highlighted that MAPCs, particularly the Multistem type, can offer significant benefits if administered early within the first 36 h after the stroke [ 55 ]. This underscores the crucial importance of optimized timing in stem cell therapies. MAPCs can act by reducing inflammation, promoting the regeneration of damaged brain tissues, and improving neurological function, thereby contributing to the recovery process after a stroke. Transcriptomic analyses have also been performed, providing important insights into the differences in differentiation potential between MAPCs and traditional MSCs [ 56 ]. These analyses have revealed that MAPCs show a greater inclination towards endothelial differentiation, namely the formation of cells that comprise blood and lymphatic vessels. This characteristic has been supported by in vitro experiments, such as Matrigel plug tests, which simulate the formation of blood vessels in a three-dimensional environment. MAPCs thus appear to express genes that are involved in angiogenesis, the process through which new blood vessels are formed from pre-existing ones, promoting tissue growth and repair [ 57 , 58 ]. On the other hand, MSCs seem to show a greater propensity towards differentiation into cartilage (chondrogenic) and bone (osteogenic) tissue cells. In summary, transcriptomic analyses have highlighted that MAPCs and MSCs present significant differences in their differentiation potential, with the former showing a greater inclination towards blood vessel formation and the latter towards the formation of cartilage and bone tissues. These differences can have crucial implications in the context of regenerative medicine, allowing for the targeted use of each cell type based on the specific needs of the patient and the pathological condition to be treated. In conclusion, MAPCs exhibit exceptional characteristics that make them valuable in regenerative medicine. Their ability to differentiate into a wide range of cell lineages, together with their immunomodulatory properties and distinct transcriptomic profiles, makes them versatile players in the treatment of a variety of pathologies. Research efforts continue to fully explore and exploit the therapeutic potential of MAPCs, with the aim of improving the health and quality of life of patients suffering from chronic diseases and severe injuries.

Small blood stem cells (SBSCs)

Identified in human peripheral blood, Small Blood Stem Cells (SBSCs), as reported by Filidou et al. [ 44 ], exhibit specific characteristics and differentiation potential, solidifying their significance in the landscape of stem cell biology. SBSCs showed bulk in vitro trilineage differentiation as demonstrated by RT-qPCR and ICC, while specific details about clonal in vitro trilineage differentiation and bulk in vivo differentiation are not provided (Table 1 , Fig. 1 ).

The population of SBSCs is distinguished by its unique expression profile, encompassing pluripotent embryonic markers, hematopoietic markers, and mesenchymal markers. This heterogeneity suggests a multifaceted nature of SBSCs, contributing to their potential in various biological processes.

Notable markers and factors associated with SBSCs encompass pluripotent and embryonic markers, exemplified by the expression of NANOG, SSEA-3, SSEA-4 and CXCR4 highlighting their potential for multilineage differentiation. SBSCs exhibit a distinctive co-expression of hematopoietic markers (CD45) and mesenchymal markers (CD90, CD29, CD105, PTH1R), suggesting their association with both blood cell development and mesenchymal lineage differentiation (Table 1 ). Quantitative proteomic profiling of SBSCs has identified diverse stem cell markers, including CD9, ITGA6, MAPK1, MTHFD1, STAT3, HSPB1, and HSPA4, enriching the understanding of their molecular composition (Fig. 1 ). Moreover, SBSCs harbor transcriptional regulatory complex factors like STAT5B, PDLIM1, ANXA2, ATF6, and CAMK1, contributing to their regulatory capabilities. This comprehensive expression profile underscores the heterogeneity and versatility of SBSCs, positioning them as a unique subset of stem cells with the potential to play a pivotal role in diverse biological processes. The isolation of SBSCs involves a protocol with serial centrifugation, facilitating their separation and collection from peripheral blood [ 45 ]. Specific details about the immunomodulatory capacity of SBSCs are not provided, highlighting avenues for further exploration to comprehensively understand their therapeutic potential in regenerative medicine. This characterization emphasizes the importance of various attributes for the evaluation and potential application of these stem cell populations.

Anyway, recent findings investigate the safety and tolerability of SBSC in dental implantation for patients with severe bone defects. Nine patients received different doses of SB cells, and evaluations were conducted through computed tomography (CT) scans and comprehensive chemistry panel testing. The trial, spanning six months, revealed no severe adverse effects, with observed improvements in bone mineral density (BMD) and stress levels. Elevations in specific cytokines and chemokines indicated SBSC-triggered responses for local tissue repair [ 46 ]. The findings support the well-tolerated use of SB cells in dental implantation, suggesting their potential for accelerating osseointegration in high-risk patients.

Coordinating embryonic, hematopoietic, and mesenchymal markers, along with the presence of various stem cell-related factors, accentuates the intriguing nature of SBSCs, warranting further investigation in the realm of stem cell research.

Markers and methodologies used for isolation

Analyzing the surface markers of the five considered stem cell populations and isolation methods, SSEA-3 emerges as a key marker extensively used in the isolation process. SSEA-3 plays a pivotal role in identifying and purifying these stem cell populations [ 16 ].

The chemokine receptor CXCR4 has been identified as a relevant marker associated with VSELs. CXCR4, also known as C-X-C chemokine receptor type 4, plays a role in the migration and homing of stem cells. CXCR4 is expressed on the surface of VSELs, and its interaction with its ligand, SDF-1 (stromal cell-derived factor 1), is considered crucial for the mobilization and homing of VSELs in various tissues [ 32 ]. This interaction is implicated in the trafficking of VSELs to areas of tissue damage or injury, where they may contribute to regenerative processes. The presence of CXCR4 on VSELs is a notable characteristic and contributes to the understanding of the homing and migration mechanisms that these stem cells employ.

CD133, also known as prominin-1, is a surface marker associated with VSELs. CD133 is a glycoprotein and is often utilized as one of the distinctive markers for isolating and characterizing VSELs.

In addition to SSEA-3 and CXCR, several other markers have been mentioned for isolating specific populations of stem cells. For instance, CD45 and CD90 have been identified as co-expressed markers in some SBSCs, emphasizing their association with blood cell development. CD29, CD105, and PTH1R have been recognized as mesenchymal markers expressed by SBSCs, indicating their ability to differentiate into mesenchymal lineages.

For MIAMI cells, CD122, CD29, CD63, CD81, CD164, CD90, and SSEA-4 have been cited as surface markers. These markers provide a distinctive profile for the identification and characterization of MIAMI cells. In the context of MAPCs, markers such as CD44, CD13, CD73, CD90, CD105, CD31, CD49d have been indicated as distinguishing elements.

Notably, methods such as Fluorescence-Activated Cell Sorting (FACS) and Magnetic-Activated Cell Sorting (MACS) have been employed for their precision in isolating cells expressing specific markers, like SSEA-3 [ 17 ]. These techniques enable the attainment of a more homogenous cell population, concentrating solely on those cells expressing the targeted marker. In contrast, the isolation method involving bone marrow under low oxygen tension (3% O2) emphasizes a distinct approach, suggesting the importance of the microenvironment in which stem cells reside.

FACS and MACS are particularly advantageous in achieving a higher degree of purity in isolated populations, ensuring that the isolated cells predominantly express the desired surface markers. This precision is crucial for subsequent analyses and applications, enhancing the reliability of research outcomes. On the other hand, methods like isolation from bone marrow under low oxygen tension might yield more heterogeneous populations, potentially capturing a broader range of stem cells with diverse characteristics.

The choice of isolation method significantly influences the purity and homogeneity of the obtained stem cell populations. While FACS and MACS offer a more defined and targeted approach, other methods might capture a broader spectrum of stem cell phenotypes.

Role of cell cycle phases in the isolation of pluripotent stem cells

The dynamic nature of stem cells, as they undergo cycling, implies a constantly changing phenotype. This characteristic serves as a protective mechanism, preventing catastrophic toxicity by allowing stem cells to exhibit different phenotypes at relatively short intervals during the cell cycle. The concept of a "stem cell calculus" is proposed, wherein changes in phenotype throughout the cell cycle represent individual components, and the overall outcome is an integration of these changes. Various studies on different stem cell types align with this model. Notably, research on highly purified LRH stem cells, even when isolated at different cell cycle points, has revealed significant heterogeneity. This observed heterogeneity, while present at the cellular level, still demonstrates overall patterns of differentiation. An analogy is drawn to the decay of radioactive substances, where individual atomic behavior appears random, but when observed as a whole, it follows a predictable pattern. This suggests that the regulation of the stem cell population as a whole, rather than individual cells, involves control mechanisms influencing birth and death probabilities [ 8 , 59 , 60 , 61 ].

This perspective raises questions about the previously-dismissed significance of the stem cell assay CFU-s (Colony-forming Unit Spleen), as it did not correlate with studies on purified stem cells. Given the observed heterogeneity in purified stem cells, the importance of CFU-s as a stem cell assay may need reconsideration. Recent emphasis on single-cell RNA analysis has revealed heterogeneity in different cell populations, including murine hematopoietic stem cells. Even in highly purified cells, small cell cycle progressions likely contribute to observed heterogeneity [ 62 ].

The proposed model suggests the existence of a universal stem cell encompassing hematopoietic LT-HSC (long-term hematopoietic stem cells) and various non-hematopoietic stem and progenitor cells, forming a continuum related to the cell cycle [ 8 ]. The differentiation of this stem cell relies on cell cycle-related changes in differentiation potential, illustrated by marker expressions like B220 and Gr-1, along with data on megakaryocyte development. The stem cell's tissue residence, modulated by extracellular vesicles, plays a crucial role, allowing transformation into non-hematopoietic tissue-specific stem cells. This model accounts for constant heterogeneity in different stem and progenitor cell classes, attributing it to continual phenotypic changes as the stem cell progresses through the cell cycle. The model is conceptualized as a stem cell calculus, where cycle-related phenotype changes represent derivatives, and the overall population outcome is the integral. While previous studies have provided valuable insights into purified LT-HSCs at specific cell cycle phases, future progress in the field involves characterizing the entire stem cell population.

This may lead to stem cell misclassification and identification, see the discussion.

The analysis of the five stem cell populations highlights several common features that are of particular interest in the context of regenerative medicine. Firstly, Multilineage-differentiating Stress Enduring (MUSE) cells, Very Small Embryonic-Like (VSEL) Cells, Small Blood Stem Cells (SBSC), Marrow Isolated Adult Multilineage Inducible (MIAMI) Cells, and Multipotent Adult Progenitor Cells (MAPC) share the presence of pluripotent embryonic markers and the ability to differentiate into a wide range of cell types, spanning the three germ layers. The notable similarity in differentiative potential suggests a possible common origin, even if contrasting data are present in literature on this subject.

MUSE cells are the most extensively studied cell types among the five above reported stem cells and hold promise for regenerative medicine. These well-characterized cells exhibit extraordinary potential for repairing damaged tissues. Similarly, VSELs have also been the focus of intense research and possess equally intriguing characteristics. Both cell types share several key features: MUSE cells and VSELs express the SSEA-3 antigen [ 63 , 64 ], which plays a role in cellular functions and differentiation; both cell types can migrate to damaged tissues, contributing to tissue repair; these cells demonstrate remarkable resilience to environmental stressors and adverse conditions. However, there are some notable differences between them. MUSE cells are mainly derived from mesenchymal tissues, while VSELs are believed to be derived from primordial germ cells or other embryonic precursors [ 65 ]. VSELs are exceptionally small, with diameters ranging from 3 to 5 µm, whereas MUSE cells are reported to be larger.

The extremely small size reported for VSEL, ranging from 3 to 5 µm, raises questions and triggers skepticism within the scientific community [ 37 ]. Cells of such diminutive dimensions are seldom encountered, and the presence of cells this small within the context of VSELs has been a subject of debate. The rarity of cells with such minuscule sizes in the cellular landscape introduces a level of skepticism regarding their actual existence and biological potential. Concerns have been voiced within the scientific community regarding the possibility that measurements of VSEL sizes may be influenced by various analytical techniques, emphasizing the need for further characterization of phenotype and isolation methodologies to more conclusively establish the true nature and size of these particular cells.

Despite these differences, both MUSE and VSEL cells offer exciting avenues for regenerative therapies, and ongoing research aims to harness their potential for treating various diseases and injuries.

In a recent paper by Oguma et al. [ 66 ], a comprehensive analysis of the transcriptome of MUSE cells at the single-cell level was conducted, drawing a comparative assessment with the transcriptome of MSCs. The study focused also on evaluating the expression profiles of various markers associated with VSELs within both MUSE cells and MSCs. VSELs, as defined by Shin et al. (2012), are characterized by their positivity for CXCR4, along with the expression of epiblast-related markers (GBX2, FGF5, NODAL) and primordial germ cell-related markers (DPPA3 [Stella], PRDM1 [Blimp1], PRDM14), while being negative for PTPRC (CD45). Intriguingly, neither MUSE nor MSCs expressed these specific marker genes, with the exception of FGF5, which exhibited higher expression levels in MSCs compared to MUSE [ 66 ].

VSELs also express additional markers, such as SSEA-4, and share similarities with germ cells, expressing markers like DDX4/VASA and PRDM14. In vitro, these VSELs remain quiescent, except in ascites, and become highly activated after exposure to valproic acid and follicle-stimulating hormone (FSH). VSELs spontaneously form aggregates resembling tumor-like structures or grow into larger cells resembling oocytes. Several studies propose a germinal origin for VSELs, while MUSE cells are found in both stromal tissues like bone marrow and tissues from the umbilical cord. While certain conditions may lead to uncontrolled proliferation of VSELs, resulting in tumor formation, numerous studies have demonstrated the non-tumorigenic nature of MUSE cells [ 26 , 33 ]. This stark contrast in tumorigenicity further underscores the distinctive characteristics between VSELs and MUSE cells, emphasizing the importance of comprehending their unique molecular profiles and biological behaviors for their potential applications in regenerative medicine.

This differential expression pattern provides valuable insights into the distinctive molecular profiles of MUSE cells and VSEL, emphasizing the need for a nuanced understanding of their biological characteristics and potential applications in regenerative medicine.

SBSC exhibit considerable overlap in characteristics with VSELs, except for the expression of CD45. This commonality suggests a shared profile related to pluripotency and regenerative potential. Furthermore, a comparative analysis with MUSE cells reveals intriguing parallels, as both SBSC and MUSE cells express SSEA-3. Interestingly, SBSC isolated from peripheral blood also exhibit CD45 expression, aligning them with MUSE cells in this aspect. However, a notable distinction remains in terms of cell size. These findings contribute to a nuanced understanding of the unique features and potential applications of SB cells, positioning them within the broader landscape of stem cell populations and highlighting both shared and distinct attributes.

MAPCs have attracted attention in biomedical research due to their remarkable capacity to differentiate into various cell types derived from the three embryonic germ layers: endoderm, mesoderm, and ectoderm. MUSE, VSEL, and MAPC stem cells can be isolated from stromal tissues, but MAPC cells uniquely possess the ability to be isolated from several organs. Recent studies indicate the potential presence of MAPCs in other adult tissues, such as the liver and brain, expanding their possible sources of isolation. Molecular distinctions between MAPC and other stem cells, including the differential expression of pluripotent and surface markers, may reflect the diverse origins and differentiation potentials of these cell populations. Both MUSE and MAPCs have demonstrated the ability to differentiate into a wide range of cell types; however, their effectiveness or differentiation potential may vary in specific experimental contexts or in relation to the preferred cell types. For instance, MAPCs might exhibit a greater predisposition to differentiate into specific cell types compared to MUSE cells, or vice versa, depending on experimental conditions or the cellular environment [ 58 ]. Concerning tumorigenicity, MUSE cells have been consistently described as non-tumorigenic in various studies, making them promising for clinical applications without the risk of tumor formation. In contrast, MAPCs may show tumorigenic potential in certain contexts or if not adequately controlled during culture, raising concerns about their therapeutic use.

MAPCs have emerged as a subject of controversy within the scientific community, primarily due to challenges associated with their reproducibility. The reliability and consistency of research findings related to MAPCs have been called into question, leading to the retraction of several studies that initially reported on these cells. The inherent difficulty in replicating experimental outcomes with MAPCs has raised concerns about the robustness and validity of the scientific evidence surrounding their properties and potential applications. These uncertainties underscore the importance of rigorous experimental design, standardization of methodologies, and comprehensive validation processes to address the reproducibility issues associated with MAPCs and establish a more reliable foundation for their characterization and therapeutic exploration. In summary, although MAPCs share some characteristics with the other population of stem cells, such as the ability to differentiate into different cell types, there are significant differences in their tissue origins, surface markers, tumorigenic potential, and other biological characteristics, which make them distinctive and potentially useful for different applications in regenerative medicine.

MIAMI cells are adult cells with interesting therapeutic potential but distinctive characteristics. Indeed, the isolation of MIAMI cells, to date, occurs solely from the bone marrow aspirates, while MUSE cells and VSEL can be isolated from a variety of stromal tissues. Nonetheless, these cells have sparked significant interest in the field of regenerative medicine due to their versatility and potential in treating bone lesions and musculoskeletal disorders. Unlike MUSE stem cells, known for their remarkable resistance to stress, MIAMI are not generally considered stress-resistant. This may impact their utility in clinical contexts where stress conditions are a significant factor. However, MIAMI cells have demonstrated to promote blood vessel formation and reduce inflammation and necrosis in ischemic tissues. This is attributable to the secreted factors they release into the surrounding environment, as identified by secretome analysis. Regarding surface markers, both for MIAMI and MAPC cells, the expression of SSEA-3 still needs to be evaluated.

In-depth studies on the proteome and transcriptome of these cell subpopulations could be pivotal to better understand the molecular basis of their unique characteristics and potential common origins. Identifying key expressed genes and proteins could shed light on the regulation of molecular pathways involved in pluripotency and cell differentiation.

The cell cycle plays a predominant role in influencing the differentiation capabilities of stem cells and the expression of various stem cell surface markers. In the context of the proposed universal stem cell hypothesis, a comprehensive investigation into the cell cycle phases of pluripotent stem cells isolated from stromal tissues becomes crucial. It is conceivable that the expression of specific markers in pluripotent stem cells might vary across different cell cycle phases. For instance, certain markers may be expressed during the G1 phase but not in other phases like S phase. Analyzing marker expression at distinct cell cycle stages could provide valuable insights into the regulatory mechanisms governing pluripotent stem cells. Correlating these cell cycle phases with the differentiation capacities across the three embryonic germ layers further enhances our understanding. This detailed analysis is instrumental in uncovering both similarities and differences within these stem cell populations. Ultimately, exploring the expression dynamics of stem cell markers throughout the cell cycle holds great promise for unraveling the intricacies of pluripotent stem cell behavior and refining our comprehension of their unique characteristics.

However, it is worth noting that the high variability in results across different laboratories could be attributed to technical differences in the isolation and culture procedures of these stem cells. Standardizing work methodologies could help reduce this variability and provide more consistent results, thereby facilitating a more accurate understanding of each population's intrinsic characteristics.

Taking into consideration the above-reported findings, the differences in biological properties among the various stromal stem cell populations so far described may be due to the fact that they are truly distinct cell populations (Fig. 2 ). Alternatively, it must be remembered that stem cells are inherently heterogeneous. This implies that the stem cell niche hosts different subpopulations of stem cells, each presenting subtle differences in stemness and lineage potential [ 67 ]. The isolation and cultivation procedures of the aforementioned stromal stem cells may have selected a specific stem cell subpopulation from the larger population of stromal stem cells.

Correlation Hypothesis Among Different Stromal/Stem Cell Lines: within stromal tissues and peripheral blood, various populations of multipotent and pluripotent stem cells (including MUSE cells, VSEL, MAPC, MIAMI, SBSC) exist. These populations share numerous common characteristics, suggesting potential interrelations or overlaps. Factors such as different isolation protocols, distinct cell cycle stages, or diverse niches could contribute to the isolation of these subpopulations. Each selected subpopulation (MUSE, VSEL, MAPC, MIAMI, SBSC) possesses specific progenitors and differentiation potential. Given the overlapping nature of stem cell populations, it is plausible that these features exhibit commonalities. However, further investigation is needed to determine whether stromal tissues harbor distinct subsets of stem cells with overlapping features or contains a single stem population, with subtypes, which can be isolated based on the aforementioned factors

This scenario is further complicated by the fact that every single cell population may exhibit differences according to the cell cycle stage of its components. Finally, confounding issues may also arise from differences in the evaluation of biological properties, either in vitro or in vivo .

Conclusions and future perspectives

In conclusion, multipotent/pluripotent adult stem cell (PSC) populations represent an extraordinary resource for regenerative medicine, offering therapeutic possibilities for a broad spectrum of pathologies. However, the confusion arising from the diversity of PSC types and their unique characteristics emphasizes the need to isolate and characterize these populations in common laboratories. Only through detailed analyses of the proteome, secretome, and transcriptome can we clarify the overlaps and differences between these stem cells, contributing to a deeper understanding of their origins and therapeutic potential.

The future of PSC research should focus on standardizing methodologies and conducting in-depth analyses in shared laboratories. This approach could not only reduce variability in results but also facilitate scientific collaboration to maximize the therapeutic potential of pluripotent stem cells. Furthermore, ongoing research into optimizing the timing of therapies underscores the need for further investigations to refine treatment strategies across different clinical conditions.

Abbreviations

Adipose tissue-derived stem/stromal cells

Fluorescence-activated cell sorting

Hematopoietic stem cells

Magnetic-activated cell sorting

Multipotent adult progenitor cells

Marrow-isolated adult multilineage inducible cells

Mesenchymal stem/stromal cells

Multilineage differentiating stress enduring cells

Primordial germ cells

Pluripotent stem cells

Sphingosine-1-phosphate

Small blood stem cells

Very small embryonic-like stem cells

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Figures 1 and 2 contain images generated with Biorender licensed to U.G.

The work presented herein was partly supported by grants from “fondo per la crescita sostenibile (FCS)” project MICROPOLI, n. F/200004/02/X45 and PRIN n. 2022MN7M2M. Salary of Assistant Professor for D.A. was obtained from MNESYS PNRR grant.

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Aprile, D., Patrone, D., Peluso, G. et al. Multipotent/pluripotent stem cell populations in stromal tissues and peripheral blood: exploring diversity, potential, and therapeutic applications. Stem Cell Res Ther 15 , 139 (2024). https://doi.org/10.1186/s13287-024-03752-x

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REVIEW article

Stem cell therapies: a new era in the treatment of multiple sclerosis.

1 Changchun University of Chinese Medicine, Changchun, China
2 The Affiliated Hospital to Changchun University of Traditional Chinese Medicine, Changchun, China
3 Hunan Provincial People's Hospital, Changsha, China

Multiple Sclerosis (MS) is an immune-mediated condition that persistently harms the central nervous system. While existing treatments can slow its course, a cure remains elusive. Stem cell therapy has gained attention as a promising approach, offering new perspectives with its regenerative and immunomodulatory properties. This article reviews the application of stem cells in MS, encompassing various stem cell types, therapeutic potential mechanisms, preclinical explorations, clinical research advancements, safety profiles of clinical applications, as well as limitations and challenges, aiming to provide new insights into the treatment research for MS.

1 Background

Multiple Sclerosis (MS), a complex autoimmune pathology, impairs the central nervous system through inflammation, demyelination, and neuronal degradation ( 1 ). Despite advancements in our comprehension of MS, formidable challenges persist in curtailing its progression and facilitating neurorestoration. Contemporary therapeutic modalities predominantly aim at symptom mitigation and disease progression containment. However, the imperative for enhanced rehabilitation and neurorestoration solutions propels the quest for innovative, efficacious therapies ( 2 ).

In recent advancements, stem cell therapy has been recognized as a frontier with significant potential in the treatment of MS. Stem cells, characterized by their inherent ability for self-renewal and pluripotency, hold promise for regenerating damaged neural tissue, modulating immune responses, and fostering an environment conducive to endogenous repair mechanisms ( 3 ). Distinct from traditional therapeutic modalities, stem cell therapy entails the transplantation of stem cells capable of differentiating into diverse neural cell types, thereby facilitating tissue regeneration ( 4 ). Moreover, these cells secrete neurotrophic factors that enhance the survival and function of adjacent neural tissue. Critically, stem cells exhibit immunomodulatory effects that attenuate inflammatory processes, offering a novel approach to mitigating the progression of MS lesions ( 5 ). Empirical studies, including laboratory and animal model research, have demonstrated the therapeutic efficacy of hematopoietic, neural, and embryonic stem cells, indicating substantial therapeutic promise ( 6 , 7 ). Preliminary clinical trials have corroborated these findings, signaling a promising horizon for individuals afflicted with MS ( 8 ).

Although some reviews on stem cell therapy for MS exist, many lack comprehensiveness, depth, and focus on emerging therapeutic approaches. Existing reviews often concentrate on specific types of stem cells or particular MS subtypes, with limited integration and comparative analysis across different stem cell types. Additionally, there is insufficient attention given to a comprehensive assessment of preclinical and clinical research progress and in-depth discussions on the safety and limitations of current treatments ( 9 , 10 ). Therefore, this review aims to address these gaps by offering a more comprehensive and in-depth analysis.

This review systematically evaluates the potential value and application prospects of stem cell therapy in MS management. Initially, we outline the current research progress on MS, followed by an in-depth examination of the fundamental biological characteristics, sources, and associated therapeutic mechanisms of hematopoietic, mesenchymal, neural, embryonic, and induced pluripotent stem cells. We provide a detailed analysis of the latest developments in preclinical and clinical studies, emphasizing the efficacy and safety of different stem cell types in MS treatment. Furthermore, this review identifies the primary challenges and limitations faced by current treatment methods, including ethical considerations, immune rejection reactions, and regulation of neural induction differentiation. Finally, addressing these issues, we propose directions and strategic recommendations for future research, highlighting the crucial role of innovative strategies in fully harnessing the potential of stem cell therapies. This review aims to provide profound insights and guidance for the further development of stem cell-based treatments in the MS therapeutic field, promoting their broader application and integration.

2 Multiple sclerosis and current landscape of treatment

The etiology of MS remains partially understood, with prevailing consensus attributing its onset to an interplay of genetic predispositions and environmental triggers ( 11 ). The hallmark pathologies of MS encompass inflammation, demyelination, and neuronal injury. Specifically, inflammation leads to lesion formation in neural tissues; demyelination results from autoimmune assaults on the myelin sheath of nerve fibers; and neuronal damage arises either directly from prolonged inflammatory states or through secondary pathological processes ( 12 ). Clinically, MS manifests in a spectrum of symptoms, including sensory deficits, motor coordination impairment, visual disturbances, fatigue, and cognitive impairments ( 13 ). The National MS Society and the MS International Federation recognize four distinct MS subtypes: clinically isolated syndrome (CIS), relapsing–remitting MS (RRMS), primary progressive MS (PPMS), and secondary progressive MS (SPMS) ( 14 ). Given the heterogeneity in symptomatology and disease trajectory, MS exerts a profound impact on patients’ quality of life, underscoring the necessity for tailored therapeutic approaches.

The current therapeutic approaches for MS include pharmacological interventions, physical therapy, and rehabilitative measures, all directed toward mitigating disease activity, relieving symptomatic burdens, and improving overall patient well-being. Among these, Disease Modifying Therapies (DMTs) are pivotal, primarily functioning to modulate the immune response and curtail inflammatory processes, thus impeding the disease progression ( 15 ). DMTs currently encompass a variety of administration routes, including subcutaneous and intramuscular injections, oral formulations, and intravenous infusions, tailored to accommodate the diverse preferences and clinical requirements of individual patients. Despite the advances in DMTs, their application is tempered by challenges related to sustained efficacy, patient-specific response variability, safety profiles, and financial implications ( 16 ). Conventional pharmacotherapy encompasses immunomodulators, anti-inflammatory compounds, and immunosuppressive medications, aimed at orchestrating immune system activity to reduce MS progression and ameliorate symptoms. An exemplar of this approach is interferon-β, which emulates endogenous interferons to temper immune hyperactivity, thereby decelerating the disease’s trajectory ( 17 ). On the other hand, immunomodulatory agents such as acetate salts function by modulating immune activity, primarily through the suppression of T-cell functionality. Despite their efficacy, there is a risk of patients developing medication resistance over time ( 18 ). During acute flare-ups, anti-inflammatory medications like methylprednisolone, a type of glucocorticoid, are utilized to mitigate inflammation; however, their long-term application is associated with adverse effects, including diminished bone density, compromised immune function, and gastrointestinal complications ( 19 ).

Beyond pharmacological interventions, holistic treatment regimens, encompassing physical therapy, rehabilitation services, and acupuncture, are employed to improve the quality of individuals with MS ( 20 ). While the efficacy of these approaches may vary across patients, the goal of achieving substantial neural regeneration remains elusive. Collectively, current therapeutic strategies can provide symptomatic relief to some degree, yet they are encumbered by various limitations and challenges. Consequently, the exploration of innovative treatments, such as stem cell therapy, represents a promising frontier in the quest for more effective MS management solutions.

3 Foundations of stem cell therapies

Over recent decades, the landscape of MS treatment has undergone transformative advances, with the development of a diverse array of therapeutic agents that have significantly mitigated symptoms and decelerated disease progression ( 2 ). The continuous innovation and introduction of novel pharmacological treatments highlight the evolving and dynamic nature of MS research. Despite these notable strides, the quest for effective neuroprotective and neuroregenerative interventions remains pressing. In this context, the potential of stem cell therapies has increasingly gained prominence. With their inherent capacity for pluripotency and differentiation into a myriad of cell types, stem cells stand at the vanguard of neuroregenerative medicine ( 21 ), offering unprecedented prospects for addressing the complex challenges of MS.

3.1 Types of stem cells

Various stem cell categories, each with unique properties, contribute differently to therapeutic applications, underscoring the diversity and versatility of stem cell-based interventions in the clinical landscape.

3.1.1 Hematopoietic stem cells (HSCs)

HSCs primarily reside in the bone marrow and possess the capability to differentiate into various blood cell types, including erythrocytes, leukocytes, and platelets. These cells play a pivotal role in maintaining the homeostasis of the hematopoietic system ( 22 ). In clinical practice, hematopoietic stem cell transplantation (HSCT) has been proficiently utilized to restore or repair damaged immune systems, thereby restoring normal immune function ( 23 ). HSCT can be divided into two types based on the source of the donor cells: autologous hematopoietic stem cell transplantation (aHSCT), where the patient’s own cells are used, and allogeneic hematopoietic stem cell transplantation (allo-HSCT), involving cells from a donor. Due to its comparatively lower mortality risk, aHSCT is the preferred method for treating immune-mediated diseases ( 24 ). These interventions have demonstrated efficacy in the treatment of various hematological disorders, including leukemia and myelopathy ( 23 ). Despite initial attempts to directly employ bone marrow-derived hematopoietic stem cells for the treatment of neurological disorders, outcomes have been less than satisfactory. This is primarily attributed to the limited neurogenic potential of HSCs, rendering their differentiation into neuronal and glial lineages complex ( 25 ). As in Parkinson’s disease, although some studies have hinted at the neuroregenerative potential of HSCs, obstacles such as restricted neurogenic differentiation capacity, impermeability of the blood–brain barrier, and immune rejection challenges have hindered their widespread clinical adoption ( 26 , 27 ). In recent years, there has been a renewed focus on the immunomodulatory role of HCST in the treatment of neurological disorders. By transplanting healthy HSCs to modulate the activity of the immune system, attenuate inflammatory responses, and thereby shield damaged neural tissues from immune-mediated injury ( 28 ). This novel finding expands the applicability of HSCs in neurology, providing new avenues and methodologies for the treatment of neurological disorders.

3.1.2 Mesenchymal stem cells (MSCs)

MSCs are ubiquitously present in diverse biological tissues such as bone marrow, adipose tissue, and the placenta, They possess the potential for self-renewal and differentiation into mesodermal cells, capable of differentiating into various cell types including osteoblasts, adipocytes, and chondrocytes ( 29 ). Based on their source, MSCs can be classified into bone marrow-derived mesenchymal stem cells (BM-MSCs), umbilical cord-derived mesenchymal stem cells (UC-MSCs), adipose tissue-derived mesenchymal stem cells (AD-MSCs) ( 30 ), dental and oral-derived mesenchymal stem cells ( 31 ), peripheral blood-derived mesenchymal stem cells ( 32 ), muscle-derived mesenchymal stem cells ( 33 ), and lung-derived mesenchymal stem cells ( 34 ), etc. Research on these cell lineages indicates that MSCs precursors predominantly originate from perivascular cells, located in the perivascular niche, underscoring their extensive regenerative potential in adult tissues. This positions MSCs as promising therapeutic candidates for various clinical conditions ( 35 ). Notably, BM-MSCs are among the most extensively studied stem cells. Research has demonstrated that BM-MSCs serve as an effective cellular therapy for treating central nervous system (CNS) inflammation and neurodegenerative diseases ( 36 , 37 ). BM-MSCs possess anti-inflammatory properties, promote the differentiation of neural stem cells, and stimulate regeneration in damaged areas of the CNS. These beneficial effects are likely mediated through paracrine signaling mechanisms and targeted migration to the injured neural tissue ( 37 ). It is worth mentioning that dental and oral-derived MSCs, such as dental pulp stem cells (DPSCs), stem cells from human exfoliated deciduous teeth (SHED), stem cells from apical papilla (SCAP), periodontal ligament stem cells (PDLSCs), gingival mesenchymal stem cells (GMSCs), and dental follicle stem cells (DFSCs), due to their embryonic neural crest origin, exhibit significant neuroregenerative potential. Therefore, they are emerging as promising cell-based therapeutic approaches for treating brain, spinal cord, cerebrovascular, and neurodegenerative diseases ( 31 , 38 – 40 ). Despite the advantages of MSCs, their lower efficiency in differentiating into specific neural cell types limits their application in neural repair. Researchers are endeavoring to enhance the efficiency of MSC differentiation into neural cells by optimizing culture conditions and controlling differentiation pathways, aiming to further differentiate them into functional neurons for the treatment of brain and spinal cord injuries and defects ( 41 ).

3.1.3 Neural stem cells (NSCs)

NSCs exhibit pluripotency with the ability to differentiate into neurons, astrocytes, and oligodendrocytes, which positions them as an optimal cellular substrate for neurologically oriented therapies ( 42 ). NSCs are naturally concentrated in specific neurogenic niches: the subventricular zone (SVZ) adjacent to the lateral ventricles and the subgranular zone (SGZ) within the hippocampal dentate gyrus ( 43 ). The therapeutic premise of NSCs utilization hinges on their capacity for neurotrophic factor secretion and differentiation into functional neural and glial cells, thereby enabling neurogenesis and the restoration of damaged CNS territories ( 44 ). NSCs have demonstrated a propensity to migrate to inflamed demyelinated regions of the CNS and differentiate into oligodendrocytes, further underscoring their therapeutic potential ( 45 ). However, the limited endogenous reservoir of NSCs available for autologous repair remains a critical limiting factor ( 46 ). Currently, research is exploring allogeneic NSC transplantation strategies, typically derived from the human fetal central nervous system (brain and/or spinal cord). Although these tissues are harvested from selectively terminated pregnancies, ethical and religious considerations pose challenges to their accessibility and ethical utilization ( 47 ). Recent studies have reported that primary NSCs can also be isolated from the cerebrospinal fluid of infants diagnosed with severe intraventricular hemorrhage (IVH) or neural tube defects (NTD) ( 48 , 49 ). Given that these samples are typically discarded, the isolation of NSCs from them does not raise specific ethical concerns. Additionally, NSCs can be isolated from adult and fetal central nervous system biopsy or autopsy specimens. Studies have successfully isolated NSCs from various brain regions, including the cortex, SVZ, hippocampus, midbrain, and spinal cord ( 50 , 51 ). Meanwhile, advancements in pluripotent stem cell technology are unveiling pathways to derive NSC-like progenitor cells from embryonic and induced pluripotent stem cells, thereby expanding the potential applications for neural interventions ( 52 ).

3.1.4 Embryonic stem cells (ESCs)

ESCs, a class of pluripotent cells sourced from the inner cell mass (ICM) of blastocyst-stage embryos, are characterized by their indefinite self-renewal capacity and the ability to differentiate into diverse cell types, including neurons, cardiomyocytes, and hepatocytes ( 53 ). In 1981, Evans et al. first isolated mouse embryonic stem cells (mESCs) from the ICM of mouse blastocysts ( 54 ). Building on the progress in mESC research, the focus shifted to human embryonic stem cells (hESCs). Thomson et al. successfully isolated and cultured hESCs from the ICM of human blastocysts in vitro ( 55 ). Both mouse and human ESCs can maintain an undifferentiated state under culture conditions and differentiate into cells of all three germ layers, exhibiting self-renewal and pluripotency ( 54 , 55 ). However, mESCs and hESCs exhibit significant differences in morphology, transcription, and epigenetics ( 56 ). For instance, while mESCs tend to form dome-shaped structures, hESCs typically exhibit a flat morphology. Although both express the pluripotency-associated OCT4 transcription factor, OCT4 expression in mESCs is regulated by its distal enhancers, whereas in hESCs, it is primarily regulated by its proximal enhancers ( 57 , 58 ). Currently, researchers utilize a mixed culture system of LN-521 and E-cadherin to derive new hESC lines from individual blastocysts without embryo destruction. Under these culture conditions, the division rate of hESCs reaches 1:30, significantly higher than the 1:3 ratio seen with traditional methods, implying that a large number of hESCs can be obtained through fewer passages ( 59 ). With advancements in cell derivation and expansion techniques, the establishment of clinical-grade hESC banks has become feasible. A cell bank containing approximately 150 donor-derived cell lines would be sufficient to meet the therapeutic needs of most populations ( 60 ). Due to their pluripotency and compatibility with human genetics, hESCs hold vast potential for disease treatment. Particularly in the field of neurology, hESCs demonstrate significant promise. They can be directed to differentiate into neuronal cells in vitro ( 61 ) and integrate into neural tissues post-transplantation, promoting spinal cord proteomic repair and facilitating the recovery process ( 62 ). Their applications in neurological diseases, such as multiple sclerosis, are increasingly gaining attention, leveraging their differentiation capabilities and neuroprotective properties to counteract disease progression ( 63 , 64 ).

3.1.5 Induced pluripotent stem cells (iPSCs)

iPSCs are engineered from somatic cells to acquire pluripotency akin to embryonic stem cells, a breakthrough pioneered by Shinya Yamanaka in 2006. Through the introduction of a quartet of transcription factors (Oct4, Sox2, Klf4, c-Myc), mature cells such as fibroblasts or hematopoietic cells are reprogrammed into a pluripotent state ( 65 ). iPSCs’ broad differentiation capacity enables them to generate any cell type, presenting expansive utility in regenerative therapies and disease modeling ( 66 ). iPSCs originate from adult somatic cells. Various mature cell types from the human body, including umbilical cord blood cells, bone marrow cells, peripheral blood cells, fibroblasts, keratinocytes, and even cells from urine samples, can be reprogrammed into iPSCs ( 67 – 69 ). Specifically, urine samples offer an inexhaustible autologous cell source and demonstrate robust reprogramming capabilities. Given that iPSCs can be derived from an individual patient, they hold promise for circumventing immune rejection responses ( 68 ). The preparation process of iPSCs mainly involves somatic cell collection, gene transduction, cell culture, and differentiation induction. Firstly, samples are collected from the patient’s somatic cells (e.g., skin cells), and specific transcription factors are introduced to reprogram these cells into iPSCs. Subsequently, iPSCs can be expanded in vitro to form cell colonies. Lastly, scientists can guide their differentiation into the desired cell types through specific induction conditions, suitable for applications in particular therapeutic areas ( 70 ). During this process, various approaches can be employed to induce pluripotency in iPSCs, including genomic modifications to induce pluripotency, utilizing small molecules and genetic signaling pathways to promote iPSCs pluripotency, microRNAs for inducing and enhancing cell reprogramming, as well as employing chemical agents to induce and enhance the pluripotency of iPSCs ( 71 ). Consequently, unlike ESCs, iPSCs derivation circumvents ethical controversies by eschewing embryonic material, thereby offering a more acceptable alternative ( 72 ). Within neurology, iPSCs exhibit promising neuroprotective and regenerative capabilities. Neuroepithelial-like stem cells (NESCs) derived from iPSCs could stimulate damaged tissue repair and host oligodendrocyte precursor cells migration and proliferation, reduce active inflammatory cells, and promote axonal regeneration ( 73 ). Despite the burgeoning potential of iPSCs, their clinical translation is tempered by ongoing technical, safety, and efficacy evaluations, yet their research continues to pave avenues for novel neurological therapeutics.

3.2 Therapeutic potential of stem cells

3.2.1 differentiation.

Stem cells, with their inherent self-renewal and pluripotent differentiation capabilities, emerge as a potent therapeutic modality for MS. A pivotal attribute of stem cells is their ability to morph into neurons, astrocytes, and oligodendrocytes, thereby presenting a viable strategy for neural tissue restoration and cellular repair ( 42 ). Utilizing small molecules to direct the differentiation of human iPSCs and assessing cell functionality through quantification of neural-specific markers has demonstrated successful differentiation into functional spinal cord neurons ( 74 ). Furthermore, NSCs isolated from the SGZ express MAP2, Nestin, and Pax6, exhibiting self-renewal capacity and pluripotency. These NSCs proliferate into multipolar astrocytes and neuron-like cells one week post-differentiation, and differentiate into various types of neurocytes by day 10. Notably, the majority of NSCs differentiate into astrocytes and neurons, while a smaller fraction differentiate into oligodendrocytes, with their projections intertwining to form a neural network ( 42 ). The neural differentiation potential of stem cells offers promising prospects for improving neurological disorders.

3.2.2 Secretion

Stem cells demonstrate neuroprotective efficacy through the secretion of growth factors and bioactive molecules, which contribute to the mitigation of inflammatory responses, reduction of oxidative stress in neuronal cells, and establishment of a conducive milieu for neural tissue preservation ( 75 ). Research has revealed that NSCs can secrete neurotrophic factors such as nerve growth factor, brain-derived neurotrophic factor, and glial cell line-derived neurotrophic factor. These factors support axonal growth and angiogenesis in injured spinal cords, thereby promoting the repair of spinal cord injuries ( 44 ). Notably, extracellular vesicles (EVs) serve as important mediators of stem cell secretion. EVs deliver various bioactive factors via paracrine mechanisms, playing crucial roles in tissue regeneration by regulating processes such as apoptosis, inflammation, proliferation, and angiogenesis across various tissues ( 76 , 77 ). MSCs are currently the primary focus of stem cell secretome-EVs. MSC-derived EVs have been shown to counteract neuronal damage and synaptic dysfunction ( 78 ). Given this promising evidence, utilizing stem cell secretome-based therapy for neurological disorders represents an innovative strategy.

3.2.3 Immunomodulation

The immunomodulatory properties of stem cells are one of the key factors that make them attractive tools for cell therapy. Stem cells can exert their immunomodulatory function through mechanisms such as releasing anti-inflammatory factors and various immunoregulatory factors, and modulating the activity and quantity of immune cells ( 79 ). Studies have shown that extracellular vesicles derived from BM-MSCs lead to a significant increase in M2-related cytokines such as IL-10 and TGF-β levels, while levels of M1-related TNF-α and IL-12 are significantly reduced. This modulation polarizes microglia to alleviate inflammation and demyelination in the central nervous system of experimental autoimmune encephalomyelitis (EAE) rat models ( 80 ). Furthermore, Luz-Crawford et al. demonstrated that injection of MSCs in the EAE model promotes the generation of an immunosuppressive environment by inhibiting pro-inflammatory T cells and inducing CD4(+) CD25(+) Foxp3(+) regulatory T cells ( 81 ). These findings corroborate the therapeutic effects of stem cells on disease progression, which are associated with their immunomodulatory function.

The therapeutic potential of stem cells is not solely based on single actions but often involves multifaceted therapeutic effects. By combining mechanisms such as neuro-differentiation, secretion, and immunomodulation, stem cell therapy offers possibilities for comprehensive treatment approaches for multiple sclerosis ( Figure 1 ). Despite ongoing challenges and necessary advancements, the innovative nature of stem cell therapy makes it a promising candidate for future treatments of multiple sclerosis.

Figure 1 . Therapeutic potential of stem cells in multiple sclerosis. The schematic diagram succinctly outlines the therapeutic potential of stem cells in multiple sclerosis. It encompasses the primary sources of various types of stem cells and the three major mechanisms through which stem cells exert their therapeutic effects in MS treatment, including differentiation into various neural cells, secretion of trophic factors, and immunomodulation. This schematic emphasizes that stem cell therapy represents a promising therapeutic strategy for the treatment of MS.

4 Application of stem cells in the treatment of MS

Although numerous medications exist for managing MS, they predominantly focus on halting disease progression and ameliorating symptoms, yet fail to offer a curative solution ( 2 ). The hurdles of achieving remyelination and neuronal regeneration remain significant in the MS treatment paradigm. Stem cell therapy, however, has recently surfaced as a promising innovative approach, attracting considerable interest within the medical community.

4.1 Application of hematopoietic stem cells in MS

In the last two decades, HSCs has gained prominence as a leading immunomodulatory therapy for autoimmune conditions ( 82 ). Specifically, aHSCT combined with immune ablation therapy has been rigorously explored for treating aggressive and treatment-resistant MS ( 83 ). There have been reports of significant symptomatic improvements in autoimmune diseases among patients undergoing HSCT for hematological cancers. This suggests the feasibility of HSCT in MS, which may offer clinical benefits ( 84 ). However, these results require further research to confirm the exact efficacy of HSCT in the treatment of MS, thus providing new directions for MS therapy.

4.1.1 Procedure for HSCT

HSCT involves a multifaceted procedure that includes the mobilization and collection of HSCs, preparation of the patient through ablative conditioning, and the subsequent transplantation of stem cells ( 85 ). After cell collection, high-dose immunosuppressive therapy (HDIT) is employed to reduce the immune system activity in patients, thus creating a more favorable environment for HSCT. HDIT involves the use of high doses of immunosuppressive agents such as cyclophosphamide (CY), methotrexate, and antibodies to suppress the activity of the immune system and lower the incidence of autoimmune diseases ( 86 ). It is noteworthy that during HDIT, depletion of the immune system may trigger the expansion of myeloid-derived suppressor cells (MDSCs) which are a heterogeneous cell population including immature myeloid cells and the progenitor cells of macrophages, dendritic cells (DCs), monocytes, and neutrophils. These MDSCs can inhibit T-cell activity, modulate immune responses, and reduce inflammation ( 87 ). Yin, et al. found that accumulation of MDSCs might contribute to patients’ overall immune suppression and result in long-term survival without influence on the risk of recurrence after allo-HSCT ( 88 ). Therefore, the expansion of MDSCs during HDIT may create a more favorable environment for HSCT, thereby enhancing its efficacy. However, due to the severe toxicity associated with whole-body irradiation, HDIT has been phased out. Contemporary conditioning regimens largely rely on BEAM (carmustine, etoposide, cytarabine, melphalan), recognized as a medium-intensity conditioning strategy ( 89 ). Moreover, low-intensity, or non-myeloablative, regimens typically incorporate CY and ATG ( 90 ), with ongoing discussions about the optimal conditioning methodology. Subsequent to conditioning, cryopreserved HSCs are thawed and reintroduced to the patient’s bloodstream. The application of ATG at this stage aims to eliminate any residual autoreactive T cells that might have survived the HDIT. This phase marks the beginning of the patient’s recovery, characterized by a critically reduced hematopoietic cell count, necessitating prophylactic antiviral and antibacterial measures ( 91 ).

4.1.2 Mechanisms of HSCs treatment

HSCs is increasingly recognized for its potential in managing MS, yet the precise immunological pathways contributing to its therapeutic impact are not fully understood. Currently, two main hypotheses are proposed to explain its efficacy. The first and more widely accepted hypothesis suggests that HSCT’s success in MS treatment stems from its ability to ‘reset’ the immune system. By introducing healthy HSCs, HSCT eliminates the dysfunctional immune cells, paving the way for the formation of a renewed immune system. This renewal process re-establishes immune tolerance and regulatory functions, effectively curbing the patient’s autoimmune activity ( 28 , 92 ). The reconstitution of immune tolerance is thought to be facilitated by regulatory T cells, which play a key role in suppressing Th17-mediated inflammatory and autoimmune responses, thus reducing the emergence of autoreactive T cells. Following immune system reconstitution, there is a notable decline in pathogenic CD4+ Th17 lymphocyte levels. Peripheral blood CD8+ T cell counts may normalize within three months post-aHSCT, with B lymphocyte levels returning to baseline after six months ( 93 ). In patients with MS undergoing aHSCT, a significant diminution in Th17 and Th1 cell activity is observed. Research employing microarray DNA chip technology has revealed significant changes in the gene expression profiles of peripheral CD4+ and CD8+ T cell subsets after aHSCT ( 94 ). This may be due to the depletion of autoreactive cells by HSCT, followed by the replacement and replenishment of adaptive immune cells. Harris et al. evaluated the T-cell repertoire in paired cerebrospinal fluid (CSF) and peripheral blood CD4+ and CD8+ T cells from active RRMS patients undergoing aHSCT. They found that after aHSCT, over 90% of the pre-existing CSF repertoire was removed, and replaced by clonotypes generated from transplanted autologous stem cells ( 95 ). This underscores the recalibration of the immune system’s pro-inflammatory and immunoregulatory components following HSCT, facilitating the reestablishment and functional repair of the immune system in MS.

Another explanation for the therapeutic effect of HSCT may involve the prolonged T-cell depletion of the conditioning regimen, leading to persistent immune quiescence, thereby eliminating significant autoimmune activity ( 96 ). However, due to severe T-cell depletion, the incidence of infections and the risk of graft-versus-host disease (GvHD) with HSCT increase. Various conditioning regimens, including the CliniMACs system and donor lymphocyte infusions (DLIs), have been proposed to prevent the occurrence of infections and GvHD ( 97 ). Indeed, tissue-resident memory T cells, which are antigen-experienced T cells permanently residing in barrier tissues, are unlikely to be completely depleted ( 98 ). However, whether complete tissue immune cell depletion is necessary or whether the maintenance of tissue immune cells can protect patients from post-transplant complications such as infections remains a subject of profound discussion and research evidence. Future studies may elucidate the prolonged depletion of tissue immune cells post-transplantation and whether this affects clinical outcomes.

4.1.3 Clinical evidence for HSCs

A series of clinical studies have been conducted to explore the efficacy of HSCs in treating MS. Fassas et al. pioneered this approach in 1997, applying peripheral blood stem cell transplantation to patients with progressive MS. Post-transplantation, a significant reduction in CD4+ cell counts was observed across the cohort, while CD8+ cells increased by approximately 50% at the 3-month mark, gradually decreasing thereafter but remaining above baseline CD4+ levels. Neurological function, assessed via the Scripps Neurological Rating Scale (SNRS), improved, suggesting that peripheral blood HSCT is relatively safe and does not exacerbate the disease ( 84 ). This discovery marks the beginning of preliminary clinical research on HSC therapy for MS, providing a direction for subsequent more in-depth and extensive studies.

Recent studies have rigorously evaluated the efficacy of aHSCT in a cohort of 507 MS patients. This comprehensive single-center study included 414 patients with RRMS and 93 with SPMS, all treated with non-myeloablative aHSCT, and reported an impressive 5-year survival rate of 98.8% ( 99 ). Moreover, a multicenter retrospective analysis revealed that MS patients treated with aHSCT experienced no clinical relapses or further disability progression. Six months post-transplantation, MRI evaluations confirmed the stability of the treatment’s effects. Remarkably, 95% of patients showed improvements in Kurtzke Expanded Disability Status Scale (EDSS) scores, signifying enhanced neurological functions ( 100 ). The aHSCT is considered as a potential treatment for MS, becoming widely used in clinical practice and showing obvious advantages. In a single-center cohort study, Vivien Häußler et al. compared the outcomes of disease activity in patients with MS undergoing aHSCT or treatment with alemtuzumab. The study results revealed significant improvements in EDSS and cognitive function in patients receiving aHSCT treatment compared to those receiving alemtuzumab therapy, and the aHSCT group maintained longer periods of no evidence of disease activity (NEDA). These findings suggest that aHSCT may be more effective than alemtuzumab in improving overall disability and cognitive abilities in MS ( 101 ). Another investigation compared the long-term disability progression between aHSCT recipients and patients receiving standard DMTs in a cohort of active SPMS patients. This study involved 79 individuals undergoing aHSCT and 1975 receiving DMTs such as interferon-beta, azathioprine, and others. Results indicated a significant delay in the time to first confirm disability progression among aHSCT recipients, suggesting that aHSCT may slow disability advancement and enhance the probability of functional improvement in active SPMS patients compared to conventional immunotherapy ( 102 ). These studies highlight the efficacy of HSCT in the treatment of MS and its advantages over other treatment modalities, providing strong evidence for the clinical application of HSCs in MS practice.

4.1.4 Clinical safety of HSCs treatment

Current research on the safety profile of HSCT acknowledges its therapeutic successes but also highlights inherent risks, including infections and suppression of hematopoietic functions. Initial adverse effects typically involve fever and viral infections, with more delayed risks possibly encompassing autoimmune thyroiditis ( 99 , 103 ). Silfverberg et al. conducted a retrospective analysis of 174 RRMS patients undergoing aHSCT, revealing that among 149 baseline disability patients, 54% showed improvement and 37% remained stable. Additionally, febrile neutropenia was the most common adverse event, with no treatment-related deaths reported ( 104 ). In a retrospective single-center observational study of all MS patients undergoing HSCT, 43% of patients showed sustained improvement in EDSS scores, 17% were diagnosed with autoimmune thyroid disease post-surgery, and 43% of women experienced amenorrhea and ovarian failure without any reported fatalities ( 105 ). Despite acceptable adverse events, the use of HSCT for MS treatment yields a higher benefit-to-risk ratio. Contemporary studies increasingly prioritize evaluating the safety and enduring impacts of HSCT, with a particular focus on reducing adverse reactions through refined dosing and drug regimens. Recent analyses have scrutinized the risk of secondary autoimmune events after various preconditioning protocols. Specifically, the incidence of complications was higher in myeloablative busulfan-based and non-myeloablative protocols, recorded at 18 and 7.7%, respectively. Conversely, the BEAM-aHSCT protocol exhibited a substantially reduced risk, at less than 1% ( 106 ). Further examination of BEAM-ATG and Cy-ATG approaches revealed similar risks, with a notable increase in secondary autoimmune thyroiditis among a cohort of 139 aHSCT recipients. The latest cohort study observed an increase in secondary autoimmunity rates post-aHSCT from 6% ( 107 ) to 17% ( 105 ), underscoring the need for vigilant monitoring and management of these risks. These findings are crucial for shaping future MS treatment protocols.

It is noteworthy that the risk of immune rejection poses a significant barrier to stem cell therapy, particularly for MS patients with hyperactive immune responses. Post-transplant GvHD remains a major cause of treatment failure and increased mortality rates in HSCT ( 108 ). Predicting the occurrence of immune rejection can be facilitated by pre-transplantation assessment of donor-derived hematopoietic stem cell expression markers, such as IL12 and IFNγ ( 109 ), thereby enabling conditioning or mobilization of patients to enhance the effectiveness and safety of HSCT. However, further research is needed to explore the incidence and risk of immune rejection after HSCT in MS, as well as effective measures to prevent its occurrence.

4.2 Application of mesenchymal stem cells in MS

The use of MSCs therapy is one of the rapidly developing branches of regenerative medicine. The simplicity of obtaining MSCs, along with their low immunogenicity and immunomodulatory capabilities, means they can be transplanted into autologous and allogeneic systems ( 110 ). Utilizing MSCs for stem cell therapy has shown promising prospects in the treatment of MS.

4.2.1 Mechanisms of MSCs treatment and preclinical evidence

Although the exact mechanisms underlying the therapeutic benefits conferred by MSCs remain to be fully elucidated, MSCs exhibit potential therapeutic efficacy due to their neuroregenerative, neuroprotective, and immunomodulatory properties ( 111 ). BM-MSCs have been shown to possess neuroprotective and remyelinating abilities under certain experimental conditions. Studies have revealed that BM-MSCs can migrate to damaged CNS in chronic and relapsing–remitting EAE mouse models, reducing injury severity, and increasing oligodendrocyte lineage cell presence in the lesion area, thus promoting functional recovery. Additionally, BM-MSCs also influence the host’s immune response, characterized by a decrease in inflammatory T cells, including interferon-γ-producing Th1 cells and interleukin-17-producing Th17 cells, and an increase in anti-inflammatory T cells, such as interleukin-4-producing Th2 cells ( 112 ). Moreover, transplanted MSCs can inhibit demyelination and stimulate remyelination, with newly formed myelin sheaths observed around axons in the corpus callosum and spinal cord during acute EAE ( 113 ). Transplantation of MSCs derived from full-term human placenta (PDMSCs) reduces brain inflammation and neurodegeneration in EAE rats, significantly improving disease course, and significantly expressing human brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), and neurotrophin-3 (NTF3) ( 114 ). The phenomenon of gaining direct neural support through the expression of neurotrophic factors post-MSCs implantation has garnered widespread attention.

Recent researchers have termed the mechanism by which MSCs exert neuroprotective effects through the secretion of bioactive substances as MSC-secretome ( 115 ). The MSC-secretome comprises cytokines, growth factors, microRNAs, etc., encapsulated in EVs such as exosomes ( 116 ). A study by Bai et al. demonstrated that hepatocyte growth factor (HGF) secreted by MSCs could improve memory defense and functional recovery in EAE mice, promoting the development of oligodendrocytes and neurons, and playing a crucial role in remyelination ( 117 ). Gratpain et al. found that SCAP can reduce the expression of pro-inflammatory markers in microglial cells by modifying the miRNA content of their secreted EVs during their study on the impact of SCAP secretome on microglial cells ( 118 ). Furthermore, hPDLSCs from RRMS patients can modulate the expression of inflammatory cytokines (TNF-α, IL-10), neuroprotective markers (Nestin, NFL70, NGF, GAP43), and apoptotic markers (Bax, Bcl-2, p21) in mouse motoneurons. Importantly, the EV from hPDLSC significantly express anti-inflammatory cytokines IL-10 and TGF-β. These findings suggest that hPDLSCs from RRMS patients exhibit immunosuppressive effects on inflamed motor neurons ( 119 ). A recent meta-analysis summarized the therapeutic effects of MSC-EVs in rodent models of MS, showing that MS animals benefited from MSC-EVs treatment, significantly improving clinical symptoms and delaying disease progression ( 120 ). Although preclinical studies suggest that MSC-EVs can improve MS, several questions remain unanswered regarding the timing, route, and dosage of MSC-EVs administration. Ahmadvand Koohsari et al. found that intravenous injection of human umbilical cord MSC-derived extracellular vesicles (hUCSC-EVs) reduced pro-inflammatory cytokines such as IL-17a, TNF-α, and IFN-γ, and leukocyte infiltration while increasing anti-inflammatory cytokines IL-4 and IL-10, thereby alleviating EAE symptoms ( 5 ).

MSCs possess potent immunomodulatory properties and can promote allograft tolerance ( 121 ). Zhang et al. found that MSCs can reduce neuroinflammation in EAE mice by increasing the M2 phenotype of microglia and decreasing their M1 phenotype and associated cytokines ( 122 ). Transplantation of BM-MSCs improves the immune mechanisms of EAE, including inhibiting T cell proliferation and activation, reducing the production of inflammatory cytokines, and modulating macrophage responses, particularly macrophage polarization, thereby preventing the onset of EAE ( 123 ). These findings broaden our understanding of MSCs transplantation in regulating T cell and macrophage immune responses. Additionally, MSCs can inhibit the proliferation of pro-inflammatory cell subsets (Th17 and Th1) and reduce the Th1/Th2 ratio of helper T cell subsets, promoting anti-inflammatory features by activating Treg cells ( 124 ). MSC-induced Treg cell activation is achieved by increasing the demethylation of Treg-specific demethylated regions (TSDR) and upregulating the expression of the Runx composite genes in TSDR, including Foxp3 (Runx1, Runx3, and CBFB) ( 125 ). MSC-induced Tregs are believed to be mediated by the secretion of PGE2, TGFβ1, IL10, and soluble human leukocyte antigen-G (sHLA-G) ( 126 ). The balance between Treg cells and T cells determines the effectiveness of immunotherapy, emphasizing the importance of MSCs as tools for regulating autoimmunity and treating MS.

4.2.2 Clinical evidence for MSCs

Insights from EAE treatments have propelled MSCs therapy into clinical trials. In a pioneering clinical study, autologous MSCs therapy was administered intrathecally to 10 PMS patients, with monitoring periods ranging from 13 to 26 months. Autologous MSCs therapy led to a modest improvement in clinical symptoms ( 127 ). Small-scale studies have provided supporting data on the safety and potential efficacy of single-dose MSCs therapy. Bonab et al. reported favorable clinical or MRI outcomes in 15 out of 25 patients, suggesting MSCs therapy as a viable option for MS patients unresponsive to standard treatments ( 128 ). The International Mesenchymal Stem Cell Transplantation Study Group (IMSCTSG) initiated a Phase I/II trial to evaluate the efficacy of autologous MSCs therapy in MS patients. Participants were divided into two cohorts, one receiving an intravenous infusion of autologous bone marrow-derived MSCs and the other a matching placebo. The trial demonstrated that MS patients receiving MSCs therapy showed a reduction in the number of new lesions and a significant decrease in lesion volume within six months of treatment ( 129 ). Neurofilament light chain (NF-L) and the chemokine receptor CXCL13 are important biomarkers for assessing MS. Karussis et al. conducted a double-blind randomized phase II clinical trial to evaluate the levels of neurofilament light chain (NF-L) and CXCL13 in the CSF of patients with progressive MS following treatment with MSCs. The results revealed a decrease in NF-L and CXCL13 levels in the CSF of patients 6 months after MSCs transplantation. The reduction in NF-L levels was significant, but the decrease in CXCL13 levels did not reach statistical significance ( 130 ). Therefore, MSCs transplantation may have neuroprotective effects on patients with MS.

Building upon the initial promising outcomes of MSCs therapy in the treatment of MS, researchers focus on exploring the diverse administration methods of MSCs for MS management. In a Phase II study, employing a randomized, placebo-controlled framework, Llufriu et al. explored changes in clinical assessments, brain MRI findings following intravenous MSCs therapy. The results confirmed the safety of the procedure and suggested a reduction in inflammatory MRI markers six months after treatment ( 131 ), providing a foundation for further investigation into MSCs therapy’s therapeutic potential in MS management. Mohyeddin Bonab et al. found that intrathecal injection of MSCs could ameliorate the condition of MS patients. However intrathecal delivery of MSCs did not alter cytokine profiles but resulted in an uptick in regulatory T-cell counts and a reduction in lymphocyte proliferation rates ( 132 ). Petrou and Kassis et al. investigated the safety and clinical efficacy of MSCs transplantation in patients with RRMS and progressive MS, as well as evaluating the optimal route of administration. Following a 14-month study involving 48 patients with MS, they found no treatment-related serious safety concerns among those who received MSC transplantation. Compared to the placebo group, recipients of bone marrow mesenchymal stem cell transplantation experienced reduced disease relapse rates and demonstrated more beneficial therapeutic effects on imaging and cognitive tests. Additionally, regarding the route of administration, intrathecal delivery outperformed intravenous administration across multiple disease parameters ( 133 ). Although intravenous and intrathecal administration of MSCs has shown distinct therapeutic advantages, the optimal route of administration for MSCs therapy in MS has not been sufficiently validated. Furthermore, active exploration of effective management strategies for MSCs should be pursued to expand their application in MS treatment.

Research on the therapeutic use of MSCs for MS includes both autologous and allogeneic sources. In MS clinical trials, there is a predilection for allogeneic MSCs harvested from fetal tissues such as placenta, amniotic epithelial cells, umbilical cord, umbilical cord matrix, and Wharton’s jelly ( 134 ). A Phase II trial involving repeated intravenous infusions of UC-MSCs reported a decrease in clinical symptoms and relapse frequency in MS patients, with serum analyses indicating a shift from a Th1 (pro-inflammatory) to a Th2 (anti-inflammatory) immune response ( 135 ). Additionally, a combined Phase I/II study focusing on SPMS patients observed a decline in relapse rates and/or lesion intensity, along with clinical score improvements following UC-MSCs therapy ( 8 ). These findings underscore the importance of further exploring the therapeutic potential of MSCs from different sources in the treatment of MS.

4.2.3 Clinical safety of MSCs treatment

Regarding treatment safety, earlier studies affirm the general safety of MSC transplantation in MS patients, with clinical data showing minimal adverse effects. However, some reports highlight potential mild side effects, including fever and headaches. A multicenter placebo-controlled study corroborated that intravenous MSCs administration does not influence the number of lesions ( 136 ). A recent meta-analysis reviewed adverse events in various disease populations following MSCs administration, revealing that the therapy is safe and closely associated only with mild adverse reactions such as short-term fever, local adverse events at the administration site, constipation, fatigue, and insomnia ( 137 ). In a study conducted by Danbour et al., within a Phase I/IIa prospective clinical trial framework, the safety and practicability of using BM-MSCs for treating MS were assessed. The findings revealed that the patients exhibited good tolerance to the treatment regimen, with improvement trends noted in all other assessments, and no significant adverse events occurred ( 36 ). It is noteworthy that in a randomized, double-blind phase II clinical trial conducted by Ucelli et al., the viewpoint opposing the use of BM-MSCs for treating active MS was presented. This study conducted at 15 sites in 9 countries, and aimed to evaluate the safety, tolerability, and efficacy of autologous BM-MSCs. They reported 213 adverse events, with the most common being infections. Furthermore, no serious adverse events were observed in the BM-MSCs transplantation group compared to the placebo group. Their study suggest that BM-MSCs therapy is safe and well-tolerated. However, at the 24-week mark, MSCs transplantation did not improve acute inflammation in MS patients as assessed by gadolinium-enhancing lesions and MRI surrogate marker. Therefore, further research is warranted to elucidate the effects of BM-MSCs on tissue repair of MS ( 138 ). Recent research has pivoted towards autologous mesenchymal stem cell-derived neural progenitor cells (MSC-NP) as an alternative to BM-MSCs, aiming to reduce ectopic differentiation risks in the CNS post-transplantation. Initial results from a Phase I trial indicate that autologous MSC-NP transplantation is not only safe but also well-tolerated. Further investigations reinforce the positive safety and efficacy profile of MSC-NP transplantation, offering substantial evidence of its viability as an alternate therapeutic option ( 139 ).

4.3 Application of neural stem cells in MS

4.3.1 mechanisms of nscs treatment.

The beneficial effects of NSCs are attributed to a variety of mechanisms, such as cellular replacement, immunomodulation, support of endogenous repair through nutritional factors, and enhancement of progenitor cell differentiation ( 140 ). NSCs possess the ability to differentiate into key neural cell types, including neurons, astrocytes, and oligodendrocytes ( 42 ). In the EAE model, NSCs are known to become activated and migrate towards areas of inflammation and demyelination within the central nervous system, where they can differentiate into oligodendrocytes, offering therapeutic promise ( 141 ). Brown et al. found that NSCs homed to the central nervous system and potentially differentiated into neural derivatives, promoting neurogenesis and myelination through modulation of the BDNF and FGF signaling pathways. Additionally, NSCs were implicated in regulating Treg and Th17 cell levels in EAE mice, inducing anti-inflammatory responses and reducing immune infiltration ( 45 ).

Some research suggests that NSCs exhibit immunomodulatory effects both locally and systemically, leading to decreased perivascular cell infiltration, lower CD3+ cell counts, and reduced expression of ICAM-1 and LFA-1 ( 142 ). Additionally, an increase in Treg cell populations has been noted in both the brain and spinal cord ( 143 ), highlighting another dimension of NSCs’ therapeutic potential. Notably, intravenous NSC transplantation has been shown to reduce the presence of CD3+ T cells and Mac3+ macrophages within the spinal cord, indicating a direct immunomodulatory effect ( 144 ). NSCs further exhibit the capacity to inhibit T-cell proliferation and cytokine production. Supporting data points to the role of soluble mediators in NSCs’ immunosuppressive functionality, with the leukemia inhibitory factor (LIF) emerging as a key factor in this immunomodulatory mechanism ( 145 ).

Different studies have indicated that neural stem cells can regulate central nervous system development and function by producing neurotrophic factors such as NGF, vascular endothelial growth factor (VEGF) ( 146 ), neurotrophin-3 (NT3) ( 147 ), and insulin-like growth factor (IGF)-1 ( 148 ). The “secretome” of NSCs and its correlation with disease improvement in animal models of neurodegenerative diseases have recently gained significant attention. Lee et al. found that NSCs cultured in vitro could produce neurotrophic factors, including BDNF, NGF, and VEGF. Neural stem cells migrate extensively from the injection site and differentiate into neurons and glial cells. Moreover, spatial memory impairment in treated mice showed some improvement ( 146 ). However, the correlation between the secretome of neural stem cells and MS has been poorly studied, requiring further research to elucidate the complex molecular signaling regulated by the NSCs secretome.

4.3.2 Preclinical evidence for NSCs

The therapeutic potential of NSCs in MS has been demonstrated through a range of preclinical studies. In EAE, the administration of NSCs, whether via intravenous infusion or direct transplantation into the lateral ventricles from the SVZ, has led to significant functional improvements across various disease stages, including pre-onset, onset, and peak phases ( 149 ). Additionally, during the chronic phase of EAE, intravenous NSC delivery has been shown to enhance functional recovery by inducing apoptosis in pro-inflammatory T cells and reducing the infiltration of inflammatory immune cells ( 150 ). Peruzzotti-Jametti et al. have shown that NSCs can alter the pro-inflammatory behavior of mononuclear phagocytes (MPs) by secreting anti-inflammatory prostaglandin E2 (PGE2) and sequestering the extracellular immunometabolite succinate. This interaction prompts a metabolic shift in MPs, facilitated by direct contact between NSCs and MPs in the meninges’ perivascular areas. This metabolic reprogramming contributes to the reduction of chronic neuroinflammation in EAE mice, thereby supporting functional recuperation ( 151 ). In EAE models using non-human primates, hNSCs have demonstrated therapeutic efficacy, markedly reducing disease severity, improving functional outcomes, and extending survival ( 152 ). Following xenogeneic transplantation, hNSCs were found to localize around blood vessels in inflamed areas of the CNS, effectively inhibiting T cell proliferation and dendritic cell maturation ( 145 ). While initial expectations centered on hNSCs differentiating into neural cells and integrating into the damaged CNS, recent preclinical findings suggest that their therapeutic effects are primarily mediated through immunomodulation, enhancement of neuroprotection, and restoration of internal homeostasis ( 153 ). In conclusion, while preclinical studies have demonstrated the therapeutic potential of NSCs in MS, primarily through immunomodulation and neuroprotection, their clinical translation faces limitations. The forthcoming discussion will explore clinical evidence regarding NSCs therapy in MS treatment.

4.3.3 Clinical evidence and safety for NSCs

Clinical studies on NSCs therapy for MS have not yet reached a stage of widespread enthusiasm. Current clinical research on NPCs largely focuses on NPCs derived from mesenchymal stem cells (MSC-NP). A Phase I clinical trial evaluated the safety and tolerability of autologous MSC-NP therapy in 20 progressive MS patients. This trial confirmed the therapy’s safety, with participants showing good tolerability and no serious adverse effects reported. Mild side effects, such as temporary fever and slight headaches, were observed but typically subsided within 24 h. Furthermore, after receiving MSC-NP therapy, 70% of the participants reported enhanced muscle strength, and 50% noted improvements in bladder control ( 139 ). A comprehensive evaluation was conducted two years post-treatment to ascertain the long-term safety and effectiveness of repeated intrathecal administrations of autologous MSC-NP in progressive MS patients. Among the 20 participants who underwent MSC-NP therapy, 18 reported no long-lasting adverse effects. Notably, seven patients exhibited sustained improvements in their EDSS scores. Further analysis of cerebrospinal fluid biomarkers showed a reduction in CCL2 levels and an increase in IL-8, hepatocyte growth factor, and CXCL12 after the therapy. These changes in biomarkers might reflect the unique immunomodulatory and trophic actions of MSC-NP therapy in MS management ( 154 ). A study assessing the feasibility, safety, and tolerability of the transplantation of allogeneic human neural stem/progenitor cells (hNSCs) in SPMS involved a one-year follow-up of 15 patients. The results demonstrated that patients receiving intraventricular hNSC injections, alongside immunosuppressive treatment, experienced no treatment-related deaths or serious adverse events ( 155 ). A research team conducted a Phase I clinical trial characterized by a single-dose administration in a non-randomized, open-label format, involving the transplantation of fetal neural stem/precursor cells. These cells, derived from the cerebral tissue of aborted fetuses, were transplanted into the spinal cords of patients with progressive MS. The trial reported positive shifts in disease biomarkers among participants, without any adverse effects linked to the treatment. Three months following the procedure, significant increases in neurotrophic factors and anti-inflammatory agents were observed in the patient’s cerebrospinal fluid, indicating the potential neuroprotective effects of the transplanted stem cells ( 156 ).

These compelling results affirm the sustained safety and therapeutic potential of NSCs in treating MS. However, the limited availability of NSCs poses challenges for widespread clinical application, prompting the exploration of more accessible NSCs sources. Consequently, there is heightened interest in the preclinical study of ESCs and iPSCs as viable alternatives.

4.4 Application of embryonic stem cells in MS

4.4.1 mechanisms of escs treatment and preclinical evidence.

Due to ethical concerns surrounding hESCs research, the application of hESCs transplantation in autoimmune diseases remains a topic of debate. While the specific mechanisms by which ESCs therapy exerts its effects in MS remain to be fully elucidated, several hypotheses have been posited. These include hESCs’ differentiation into neural cell types such as neurons, astrocytes, and oligodendrocytes, their role in reducing apoptosis, modulating neurotrophic factor release, and mitigating inflammatory responses ( 157 ). In primate models of EAE, the intrathecal delivery of extramedullary mesenchymal stem cells (EMSCs) derived from hESCs led to notable improvements in clinical outcomes, reduction of brain pathology, and protection against neuronal demyelination. In contrast, the control group exhibited progressive enlargement of MRI-detected brain lesions. EMSCs demonstrated the ability to differentiate into neural cell types in the CNS, alongside an increase in the expression of genes related to neuronal markers, neurotrophic factors, and myelination processes. These results suggest that direct intrathecal administration of EMSCs can decelerate disease progression, underscoring the potential for clinical application of embryonic stem cell therapies ( 158 ). Furthermore, transplantation of neural progenitor cells derived from hESCs has been shown to alleviate clinical symptoms in EAE mice. Although transplanted neural progenitor cells were observed in the mouse brain, remyelination and the generation of mature oligodendrocytes were not observed. Clinical improvements may be attributed to immunosuppression and neuroprotective mechanisms ( 63 ). Recent studies have reported the derivation of pluripotent stem cells from mouse fibroblasts through reprogramming with specific transcription factors ( 65 ), thereby enhancing the prospect of utilizing potential autologous cell sources from hESC derivatives and avoiding ethical concerns associated with human embryo usage. Reports have demonstrated the ability of mESCs to generate NSCs in vitro using developmental cues ( 159 ), including region-specific neuronal subtypes such as dopaminergic neurons and motor neurons ( 160 ). Despite interspecies differences, insights into the neurogenic potential of mESC provide information and a platform for ESC research.

4.4.2 Clinical evidence for ESCs

One case highlighted a 34-year-old female MS patient who received hESC transplantation, with subsequent diffusion tensor imaging revealing marginal decreases in lesion sizes near the bilateral ventricles and adjacent to the right occipital lobe’s white matter. In another investigation, two patients with concurrent diagnoses of MS and Lyme Disease (LD) exhibited significant improvements in functional abilities, endurance, cognitive function, and muscle strength following hESC therapy, as assessed by diffusion tensor imaging and single-photon emission computed tomography. These outcomes suggest the efficacy and safety of hESC therapy for patients with MS and LD ( 161 ). However, the current body of evidence remains limited, underscoring the need for comprehensive clinical trials to confirm the long-term efficacy and safety of hESC therapy in MS. Research in this area continues to face various technical and ethical challenges, including issues related to the sourcing of ESCs and controlling their differentiation. Additionally, the regulatory environment surrounding the sourcing and application of ESCs, involving ethical debates and the necessity of donor consent, adds further complexity to the widespread use of ESCs. Research in this field must navigate within established legal and ethical frameworks.

4.5 Application of induced pluripotent stem cells in MS

iPSCs are a dynamic category of cells that can be reprogrammed from various somatic tissues, possessing the capability to differentiate into oligodendrocyte precursor cells (OPCs). This characteristic positions iPSCs as a promising candidate for autologous cell therapy approaches ( 162 ). Current preclinical research is actively exploring the therapeutic potential of iPSCs, with preliminary findings indicating that iPSCs-derived OPC can mitigate both clinical symptoms and pathological changes in EAE, largely through neuroprotective mechanisms rather than direct remyelination ( 163 ). The administration of iPSC-derived neural progenitor cells (iPSC-NPCs) into EAE models has demonstrated significant benefits, including reduced infiltration of inflammatory cells, decreased spinal cord demyelination, and lessened axonal damage. The therapeutic impact of iPSC-NPCs in these models is attributed to their secretion of neuroprotective factors like LIF, enhancing the survival and maturation of oligodendrocytes ( 164 ). Another study highlighted the significant decrease in T-cell infiltration and attenuation of white matter damage following iPSC-NSCs transplantation in EAE. Treatment with iPSC-NSCs also resulted in notable reductions in disease symptom scores and enhancements in motor skills, affirming the potential of iPSC-NSCs as a therapeutic option for MS ( 165 ).

Moreover, astrocytes have been shown to play multiple roles in the injury and repair processes of MS ( 166 ). Kerkering et al. differentiated iPSCs derived from BMS patients into NSCs, further differentiating them into BMS patient-specific neurons and astrocytes. They found that iPSC-derived astrocytes exerted a protective effect against TNF-α/IL-17-induced neuronal pathology. This neuroprotective effect was mediated through the JAK/STAT signaling pathway. Activation of the JAK/STAT pathway induced the production of soluble mediators such as LIF, BDNF, and TGF-β1, which exerted neuroprotective effects. Additionally, iPSC-induced astrocytes from BMS patients stabilized the TNF-α-induced NF-κB signaling pathway, thereby protecting cells from inflammatory neuronal damage ( 167 ).

With the successful reprogramming of somatic cells into iPSCs, innovative strategies for direct neural lineage conversion have been developed. The application of neural lineage-specific transcription factors (TFs) facilitates the creation of induced neural stem cells (iNSCs). When transplanted into models of EAE, iNSCs have shown the capacity to differentiate into oligodendrocytes and integrate into disrupted myelin structures in the brain ( 168 ). Yun et al. also manipulated human somatic cell reprogramming into OPCs by combining OCT4 with small molecules. They transplanted the generated iOPCs into the brains of EAE mice and observed that OPCs or iOPCs could integrate into the host nervous system by day 100 post-transplantation. They differentiated into mature oligodendrocytes, significantly ameliorating disease symptoms to levels comparable to normal mice and showing no tumorigenic effects. Moreover, transmission electron microscopy (TEM) of the brains and spinal cords of mice in the iOPC and OPC transplantation groups revealed abundant compact myelin when compared to the PBS group, indicating that transplanted iOPCs and OPCs could promote axonal remyelination ( 169 ).

Notably, there is concern that donor cells may retain epigenetic memory post-reprogramming, raising the possibility of immune rejection after transplantation. Additionally, the lengthy process of generating iPSC-derived NSCs carries the risk of introducing genetic instabilities, increasing tumorigenesis potential ( 163 ). Therefore, while iPSCs and their neural derivatives show promise in preclinical studies, significant obstacles remain in their path to clinical use. To enhance the efficacy of neural repair, it is essential to precisely guide stem cell differentiation into specific neuronal cell types, a process involving intricate control mechanisms of gene expression and signaling pathways ( 170 ). A thorough understanding of the factors regulating differentiation is crucial to ensure reliable guidance of stem cells towards functional neuronal cells. Future research is necessary to explore the ability of transplanted stem cells to maintain stable differentiation in vivo and prevent unwanted cell proliferation or differentiation.

5 Conclusion

In summary, traditional therapies for multiple sclerosis (MS) are limited by side effects and varying efficacy, contrasting sharply with the overall prospects of stem cell therapies aimed at neuroregeneration, neuroprotection, and immunomodulation. Various types of stem cells, including HSCs, MSCs, NSCs, ESCs, and iPSCs, have demonstrated significant therapeutic potential for MS in preclinical and clinical studies. Simultaneously, exploration of the effectiveness and safety of SCs in treating MS is gradually advancing. Despite the initial success of these stem cells in MS treatment, significant challenges persist, including regulation of neural induction differentiation, immune rejection, and ethical oversight. Future research needs to not only refine these areas but also explore combination therapies to enhance treatment outcomes. The development of future stem cell therapies could significantly alter the landscape of MS treatment. The path forward will require balanced collaborative efforts to translate promising preclinical findings into safe, effective clinical applications, offering new hope for patients with MS.

Author contributions

LW: Conceptualization, Resources, Supervision, Writing – review & editing. JL: Conceptualization, Resources, Supervision, Writing – review & editing. TL: Conceptualization, Resources, Supervision, Writing – review & editing. DZ: Data curation, Formal analysis, Writing – original draft. HX: Data curation, Formal analysis, Writing – original draft. ZK: Investigation, Methodology, Writing – review & editing. FP: Investigation, Methodology, Writing – review & editing. JW: Investigation, Methodology, Writing – review & editing.

The author(s) declare that no financial support was received for the research, authorship, and/or publication of this article.

Conflict of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Publisher’s note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

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Keywords: multiple sclerosis, stem cell therapy, stem cell transplantation, neural stem cells, induced pluripotent stem cells

Citation: Wu L, Lu J, Lan T, Zhang D, Xu H, Kang Z, Peng F and Wang J (2024) Stem cell therapies: a new era in the treatment of multiple sclerosis. Front. Neurol . 15:1389697. doi: 10.3389/fneur.2024.1389697

Received: 22 February 2024; Accepted: 22 April 2024; Published: 09 May 2024.

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Copyright © 2024 Wu, Lu, Lan, Zhang, Xu, Kang, Peng and Wang. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) . The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

*Correspondence: Jian Wang, [email protected]

Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.

A case of acute lung injury in a peripheral blood stem cell donor mobilized with pegylated recombinant human granulocyte colony-stimulating factor

Case Report
Published: 10 May 2024

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Lin Liu 1 ,
Ding-song Zhang 1 ,
Xue-juan Zhang 1 ,
Zhong-zheng Zheng ORCID: orcid.org/0000-0003-1965-631X 2 &
San-bin Wang 1

Pegylated recombinant human granulocyte colony-stimulating factor (PEG-rhG-CSF) has been introduced for the mobilization of peripheral blood stem cells (PBSCs). However, no cases of acute lung injury (ALI) in healthy donors have been reported, and the underlying mechanisms remain poorly understood. We first reported a case of ALI caused by PEG-rhG-CSF in a healthy Chinese donor, characterized by hemoptysis, hypoxemia, and patchy shadows. Ultimately, hormone administration, planned PBSC collection, leukocyte debridement, and planned PBSC collection resulted in active control of the donor's ALI. The donor's symptoms improved without any adverse effects, and the PBSC collection proceeded without incident. Over time, the lung lesion was gradually absorbed and eventually returned to normal. PEG-rhG-CSF may contribute to ALI in healthy donors via mechanisms involving neutrophil aggregation, adhesion, and the release of inflammatory mediators in the lung. This case report examines the clinical manifestations, treatment, and mechanism of lung injury induced by PEG-rhG-CSF-mobilized PBSCs.

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Acknowledgements

We appreciate Shanghai Tissuebank Biotechnology Co., Ltd for assistance with reviewing and editing.

This study was supported by grants from the Biomedical Major Project of Yunnan Province (No. 202102AA100011) and Yunnan Applied Basic Research Projects-Union Foundation (Nos. 202201AY070001-280 and 202201AY070001-278).

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Department of Hematology, The 920 Hospital of PLA Joint Logistics Support Force, No. 212, Daguan Road, Xishan District, Kunming, 650032, Yunnan Province, China

Lin Liu, Ding-song Zhang, Xue-juan Zhang & San-bin Wang

Shanghai Tissuebank Biotechnology Co., Ltd, No. 908. Ziping Road, #21 Building, Pudong New District, Shanghai, 201318, China

Zhong-zheng Zheng

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LL and ZDS enrolled the samples. ZXJ and ZZZ performed the genetic analysis and wrote the draft of the manuscript. ZXJ and ZZZ revised the manuscript. WSB designed the project and supervised the work. All authors have accepted responsibility for the entire content of this manuscript and approved its submission.

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Correspondence to Zhong-zheng Zheng or San-bin Wang .

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Liu, L., Zhang, Ds., Zhang, Xj. et al. A case of acute lung injury in a peripheral blood stem cell donor mobilized with pegylated recombinant human granulocyte colony-stimulating factor. Int J Hematol (2024). https://doi.org/10.1007/s12185-024-03779-z

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Received : 19 January 2024

Revised : 06 April 2024

Accepted : 15 April 2024

Published : 10 May 2024

DOI : https://doi.org/10.1007/s12185-024-03779-z

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All prospective controlled clinical studies of stem cell therapy on autism patients were included, as were trials in which stem cells were part of a complex intervention. We excluded qualitative studies, uncontrolled trials, case studies and case series, as well as trials that developed between different cell types, and studies that failed to ...
Stem cell-based therapy for COVID-19 and ARDS: a systematic review
It should be noted that eight (27.5%) studies used cell therapy as compassionate use and one (3.4%) as a proof of concept. Most studies (75%) used mesenchymal stem cell therapy in an attempt to ...
Stem cells: past, present, and future
In recent years, stem cell therapy has become a very promising and advanced scientific research topic. The development of treatment methods has evoked great expectations. This paper is a review focused on the discovery of different stem cells and the potential therapies based on these cells. The genesis of stem cells is followed by laboratory steps of controlled stem cell culturing and derivation.
case studies
Three examples of stem cell therapies have made history: the cure of X-SCID-affected Jack Crick, the cure of the Berlin patient who, with the help of stem cells, escaped both HIV and leukemia and the rescue of the butterfly child Hassan, who was close to death before genetically modified stem cell therapy saved his life and gave him a future.
Case highlights the risks of experimental stem cell therapy
A report in the journal CMAJ details the case of a 38-year-old man who developed a benign tumor on his spinal cord that his doctors linked to an experimental stem cell treatment he received 12 ...
Developing a Case Study Model for Successful Translation of Stem Cell
Cell therapies derived from pluripotent stem cells are entering the preclinical and early clinical development phase, but eventual translation faces many challenges. We describe a new approach by California to form global public-private "disease team" partnerships to enable new clinical opportunities to be evaluated in the complex regulatory environment.
PDF A Case on Stem Cell-Based Therapy
Jim and the Forgotten Embryos: A Case on Stem Cell-Based Therapy. by. Miriam Segura-Totten Department of Biology North Georgia College & State University, Dahlonega, GA. Part I - Late Night News. Sandy was barely watching the reality show on TV. Instead, she was anxiously waiting for her son Jim to arrive home for the weekend.
Stem Cell Therapy Improves Post-Stroke Motor Function
A first-in-human trial suggests that neural stem cell transplant is safe, improves motor function, and provides hope for patients with chronic ischemic stroke. This site is intended for healthcare ...
Stem Cell Therapies in Clinical Trials: Progress and Challenges
Developing a case study model for successful translation of stem cell therapies. Cell Stem Cell. 2010; 6: 513-516. Abstract; Full Text; Full Text PDF ... the C-CURE (Cardiopoietic stem Cell therapy in heart failURE) multicenter randomized trial with lineage-specified biologics. J. Am. Coll. Cardiol. 2013; 61: 2329-2338. Abstract; Full Text ...
Stem Cell Therapy Clinical Trials
A Study to Assess Adult Allogeneic Expanded Adipose-derived Stem Cells (eASC) for the Treatment of Complex Perianal Fistula(s) in Patients with Crohn's Disease Scottsdale/Phoenix, AZ . The purpose of this study is to assess the effectiveness and safety of Cx601, adult allogeneic expanded adipose-derived stem cells (eASC), for the treatment of complex perianal fistula(s) in patients with Crohn ...
Lessons learnt, and still to learn, in first in human stem cell trials
In the case where the cell therapy product (biologic) requires a non-cleared 510(k), a non-PMA device for delivery or it is integrated into the product, the FDA designates the cell therapy and delivery device be viewed as a combination product. ... explores basic discoveries in stem cell research and its application. Dr. Pera goes "beyond the ...
PDF Stem Cell Therapies for T1D: Promise and Challenges
Ø Great progress in stem cell-derived beta cell research Ø Ongoing clinical trials Ø Viable future therapy Ø Challenges remain § Directed differentiation § Variability between cell lines § Functional maturation § Need for pure beta cells vs. islet cells § Scaling up differentiation protocols § Graft survival § Immune protection
Building More Homes for Hematopoietic Stem Cells
A new study reveals how stem cell niche generation is regulated in bone marrow, which could lead to improvements in stem cell transplantation for the treatment of blood diseases. Bone marrow transplants give patients new blood stem cells to replace original diseased cells and have helped millions of people with blood disorders, including cancer.
Case Studies
Published in the International Society for Stem Cell Application ISSCA Magazine in April of 2018; Dr. Leslie Mesen from the Stem Cells Transplant Institute shares a case study showing the significant healing effect stem cell therapy provided a patient that suffered a very serious wound following a shock from 30,000 volts of electricity.
Multipotent/pluripotent stem cell populations in stromal tissues and
The concept of "stemness" incorporates the molecular mechanisms that regulate the unlimited self-regenerative potential typical of undifferentiated primitive cells. These cells possess the unique ability to navigate the cell cycle, transitioning in and out of the quiescent G0 phase, and hold the capacity to generate diverse cell phenotypes. Stem cells, as undifferentiated precursors endow ...
Evaluation of the Safety and Efficacy of Repeated Mesenchymal Stem Cell
Background: Amyotrophic lateral sclerosis (ALS) is an incurable disease. There are vigorous attempts to develop treatments to reduce the effects of this disease, and among these treatments is the transplantation of stem cells. This study aimed to retrospectively evaluate a mesenchymal stem cell (MSC) therapy cohort as a promising novel treatment modality by estimating some additional new ...
Stem cell therapies: a new era in the treatment of multiple sclerosis
Keywords: multiple sclerosis, stem cell therapy, stem cell transplantation, neural stem cells, induced pluripotent stem cells. Citation: Wu L, Lu J, Lan T, Zhang D, Xu H, Kang Z, Peng F and Wang J (2024) Stem cell therapies: a new era in the treatment of multiple sclerosis. Front. Neurol. 15:1389697. doi: 10.3389/fneur.2024.1389697
Developments in stem cell-derived islet replacement therapy for
The generation of islet-like endocrine clusters from human pluripotent stem cells (hPSCs) has the potential to provide an unlimited source of insulin-producing β cells for the treatment of diabetes. In order for this cell therapy to become widely adopted, highly functional and well-characterized stem cell-derived islets (SC-islets) need to be ...
Current Guidelines, Challenges, and Future ...
This paper reports on the research findings of semi-structured interviews with local stakeholders to investigate how they perceived and evaluated the current regulatory framework for human stem cell research in Malaysia and what might be at stake if the state continues with its current regulatory approach. Expand
Stem cell-based therapy for human diseases
Stem cell therapy is a novel therapeutic approach that utilizes the unique properties of stem cells, including self-renewal and differentiation, to regenerate damaged cells and tissues in the human body or replace these cells with new, healthy and fully functional cells by delivering exogenous cells into a patient. 7 Stem cells for cell-based ...
A case of acute lung injury in a peripheral blood stem cell donor
Pegylated recombinant human granulocyte colony-stimulating factor (PEG-rhG-CSF) has been introduced for the mobilization of peripheral blood stem cells (PBSCs). However, no cases of acute lung injury (ALI) in healthy donors have been reported, and the underlying mechanisms remain poorly understood. We first reported a case of ALI caused by PEG-rhG-CSF in a healthy Chinese donor, characterized ...
Stem Cell Therapy: From Idea to Clinical Practice
3. From Preclinical Study to Clinical Trial. In principle, any idea regarding stem cell therapy should be assessed using comprehensive studies (i.e., in vitro and in vivo) before a clinical trial is considered, and the results of these studies should be proved by competent authorities.

Stem cell case studies

Since 1988, cord blood stem cells have been used to treat a growing number of diseases and disorders.

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Growing Cartilage Using Stem Cells and 3D Printing

Researchers Investigate Use of Umbilical Cord Stem Cells for Crohn’s

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Case report: Stem cells a step toward improving motor, sensory function after spinal cord injury

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