a research paper on stem cells

Stem cells: past, present, and future

Affiliations.

1 Department of Experimental Surgery and Biomaterials Research, Wroclaw Medical University, Bujwida 44, Wrocław, 50-345, Poland. [email protected].
2 Department of Conservative Dentistry and Pedodontics, Krakowska 26, Wrocław, 50-425, Poland.
3 Department of Experimental Surgery and Biomaterials Research, Wroclaw Medical University, Bujwida 44, Wrocław, 50-345, Poland.
PMID: 30808416
PMCID: PMC6390367
DOI: 10.1186/s13287-019-1165-5

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. Quality control and teratoma formation assays are important procedures in assessing the properties of the stem cells tested. Derivation methods and the utilization of culturing media are crucial to set proper environmental conditions for controlled differentiation. Among many types of stem tissue applications, the use of graphene scaffolds and the potential of extracellular vesicle-based therapies require attention due to their versatility. The review is summarized by challenges that stem cell therapy must overcome to be accepted worldwide. A wide variety of possibilities makes this cutting edge therapy a turning point in modern medicine, providing hope for untreatable diseases.

Keywords: Differentiation; Growth media; Induced pluripotent stem cell (iPSC); Pluripotency; Stem cell derivation; Stem cells; Teratoma formation assay; Tissue banks; Tissue transplantation.

Publication types

Research Support, Non-U.S. Gov't
Cell Differentiation / genetics*
Cell- and Tissue-Based Therapy / trends*
Graphite / chemistry
Graphite / therapeutic use
Induced Pluripotent Stem Cells / transplantation*
Stem Cell Transplantation / classification
Stem Cells / classification
Stem Cells / cytology*
Tissue Scaffolds / chemistry

Open access
Published: 19 December 2018

Recent advances in stem cell therapeutics and tissue engineering strategies

Seong Gyu Kwon 1 ,
Yang Woo Kwon 1 ,
Tae Wook Lee 1 ,
Gyu Tae Park 1 &
Jae Ho Kim ORCID: orcid.org/0000-0003-4323-4790 1 , 2

Biomaterials Research volume 22 , Article number: 36 ( 2018 ) Cite this article

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Tissue regeneration includes delivering specific types of cells or cell products to injured tissues or organs for restoration of tissue and organ function. Stem cell therapy has drawn considerable attention since transplantation of stem cells can overcome the limitations of autologous transplantation of patient’s tissues; however, it is not perfect for treating diseases. To overcome the hurdles associated with stem cell therapy, tissue engineering techniques have been developed. Development of stem cell technology in combination with tissue engineering has opened new ways of producing engineered tissue substitutes. Several studies have shown that this combination of tissue engineering and stem cell technologies enhances cell viability, differentiation, and therapeutic efficacy of transplanted stem cells.

Stem cells that can be used for tissue regeneration include mesenchymal stem cells, embryonic stem cells, and induced pluripotent stem cells. Transplantation of stem cells alone into injured tissues exhibited low therapeutic efficacy due to poor viability and diminished regenerative activity of transplanted cells. In this review, we will discuss the progress of biomedical engineering, including scaffolds, biomaterials, and tissue engineering techniques to overcome the low therapeutic efficacy of stem cells and to treat human diseases.

The combination of stem cell and tissue engineering techniques overcomes the limitations of stem cells in therapy of human diseases, and presents a new path toward regeneration of injured tissues.

The growing tendency of increased life expectancy as well as increased incidence of age-related degenerative diseases and tissue damage requires the use of allogenic or autologous grafts for tissue repair. Although transplantation of tissues or cells is innovative and has been applied to a lot of treatments, its application in clinical settings is still limited [ 1 ]. Accumulating evidence suggests that stem cells can accelerate the tissue regeneration through various mechanisms. To date, a variety of stem cells, including mesenchymal, embryonic, and induced pluripotent stem cells, have been reported to promote regeneration of damaged tissues [ 2 ]. Although stem cell therapy provides a new paradigm in tissue regeneration, they have limitation in clinical application due to poor survival and differentiation potentials of the transplanted cells [ 3 ]. To overcome these limitations, tissue engineering technology has been used to improve the viability and proliferative capacity of stem cells. Tissue engineering is the use of a combination of cells, biomaterials, biochemical and physicochemical factors, and engineering technologies to improve or replace biological tissues [ 4 ]. In this paper, we will review the types of stem cells, their use in various tissues, and tissue regeneration through stem cell engineering. In addition, there are many other kinds of stem cells that can be used for tissue regeneration; however, in this review, we focus on the above-mentioned stem cells for tissue regeneration.

Types of stem cells for tissue regeneration

Mesenchymal stem cells (MSCs) can be isolated from various tissues, such as adipose tissue, tonsil, and bone marrow. MSCs show plastic adherent properties under normal culture conditions and have a fibroblast-like morphology. They express specific cell surface markers including CD73, CD90, and CD105. MSCs have the potential for self-renewal and differentiation potential into mesodermal lineages, including adipocytes, muscles, chondrocytes, and osteoblasts [ 2 ]. In addition to the differentiation potential, increasing body of evidence suggests that MSCs possess immune modulatory function and pro-angiogenic activity which are beneficial for tissue regeneration [ 5 ]. MSCs interfere with dendritic cell and T-cell function and generate a local immunosuppressive environment by secreting various immune-modulatory cytokines [ 6 ]. Moreover, MSCs promote angiogenesis by secreting pro-angiogenic factors [ 7 ]. Therefore, MSC-based clinical trials have been conducted worldwide for various human diseases, including cardiovascular, bone and cartilage, neuronal, and inflammatory diseases [ 8 ]. Several MSC-based cell therapeutics are commercially available [ 9 ], although their therapeutic efficacy is still in debate.

Embryonic stem cells (ESCs) are pluripotent stem cells derived from the inner cell mass of blastocysts, and they can differentiate to specific cell types by controlling culture conditions [ 10 ]. Recently, clinical trials were initiated to test the safety and potential efficacy of human ESCs in several diseases, including spinal cord injury, macular degeneration, diabetes and heart diseases. In 2010, Geron Corporation transplanted hESC-derived oligodendrocyte precursors, GRNOPC1, into five patients with spinal cord injury, and the clinical trial data suggest long-term safety of the therapy as well as reduced spinal cord cavitation in four of the five patients [ 11 ]. In addition, Advanced Cell Technology (MA, USA) tested human ESC-derived retinal pigment epithelium for age-related macular degeneration and Stargardt disease, a juvenile form of macular degeneration, and the clinical trial data have shown positive safety data with no tumorigenicity and improved clinical data in some patients [ 12 ]. Although ESCs have prominent advantages such as pluripotency and self-renewal potential, there are several obstacles hindering the clinical application of ESC-based cell therapeutics [ 13 ]. Because ESCs are derived from an embryo, they are allogenic cells to the patient and thus can be subjected to immune rejection. [ 14 ]. Secondly, it is difficult to induce differentiation into a desired cell type with 100% efficiency, thus a small fraction of undifferentiated cells might remain and form teratomas. Moreover, there are ethical issues because human ESCs are derived from human embryo, which has delayed clinical application of ESCs.

These ESC-associated issues were alleviated by the work of Yamanaka and colleagues on somatic cell reprogramming [ 15 ]. They demonstrated that somatic cells could be reprogrammed to a primordial stem cell state by introducing four pluripotency-inducing transcription factors. Since induced pluripotent stem cells (iPSCs) could be reprogrammed from adult somatic cells, they are free from ethical concerns [ 16 ]. Although iPSCs do not negate the risk of generating tumors, transplantation of autologous iPSC-derived cell therapeutics could help solve the immunological problem associated with transplantation of ESC-derived cells [ 17 ]. Japan’s RIKEN Institute successfully transplanted the world’s first iPSC-derived therapy into age-related macular degeneration patients [ 18 ]. However, there is a risk of neoplastic development from cells differentiated from iPSCs, because reprogramming factors are associated with the development of tumors [ 19 ].

Development of stem cell-activating growth factors and peptides

Stem cells can differentiate into different kinds of cell types in response to specific ligands or growth factors (Fig. 1 ) [ 20 ]. Direct transplantation of stem cells into injured tissues was found to be effective in animal models; however, the possibility of inducing local ischemia or thrombosis has been raised [ 21 ]. Moreover, stem cell-based cell therapy has been hampered by poor survival of transplanted stem cells in vivo. Therefore, there is a need to develop stem cell-activating factors that enhance the survival, paracrine effects, and therapeutic efficacy of transplanted stem cells. In particular, BMPs have been shown to exert novel effects on cartilage and bone regeneration in several animal experiments. It has been reported that bone morphogenetic proteins (BMPs) and bone-forming peptide-3 stimulated differentiation of MSCs to osteoblasts [ 22 , 23 ]. Among the various types of BMPs, both BMP2 and BMP7 have been shown to play important roles in bone and cartilage regeneration [ 24 , 25 ].

Stem cell differentiation in response to specific ligands or growth factors

Not only growth factors but also extracellular matrix proteins have been shown to promote the regenerative potentials of stem cells. Co-transplantation of MSCs along with collagen matrix or fibrin to the injured tissue site is now widely used clinically [ 26 ]. Periostin, an extracellular matrix protein that is expressed in the periosteum and periodontal ligaments, has been identified as a secreted protein of MSCs. Recombinant periostin protein stimulates proliferation, adhesion, and survival of MSCs in vitro, and co-implantation of MSCs and recombinant periostin protein significantly accelerates bone regeneration by increasing angiogenesis in a calvarial defect animal model [ 27 ]. Moreover, recombinant periostin and its fasciclin I domain promote therapeutic angiogenesis in a murine model of chronic limb ischemia [ 28 ]. Periostin stimulates angiogenesis and chemotaxis of endothelial colony forming cells through a mechanism involving β3 and β5 integrins. Recently, a short peptide sequence (amino acids 142–151), which is responsible for periostin-mediated angiogenesis, has been identified by serial deletion mapping of the first fasciclin I domain [ 29 ]. These results suggest that periostin can be applied for cell therapy by stimulating the pro-angiogenic and tissue regenerative potentials of MSCs.

In addition, it has been reported that co-transplantation of N-acetylated proline-glycine-proline, a peptide produced by the degradation of collagen, accelerates repair of dermal wounds by stimulating migration and engraftment of transplanted endothelial colony forming cells [ 30 ]. These results demonstrate that pro-angiogenic peptides, including periostin and N-acetylated proline-glycine-proline, promote regenerative potentials of transplanted stem cells by accelerating angiogenesis.

Stem cells engineered with nanomaterials

While growth factors and cytokines can affect the biological functions of stem cells from “outside”, there are several ways to manipulate them from “inside”, as an approach on a more fundamental level. Gene therapy using viral expression systems is a well-known traditional method for manipulating the biological functions of stem cells from “inside”. However, viral expression systems have been reported to induce immune and inflammatory reactions in host tissues, and genetic mutations in host DNA can occur [ 31 ]. Therefore, development of highly efficient non-viral expression system is important for stem cell research. For instance, reprogramming or direct conversion of somatic cells by using non-viral gene expression system have great potential for clinical application of the reprogramming cells. Replacing viruses with alternative extracellular chemicals or delivery systems can reduce tumor formation. Non-viral methods include electroporation of cell membrane or delivery of genes in a form complexed with liposome or cationic polymers. Several types of nanoparticles have been developed for non-viral delivery of reprogramming factors into cells. These nanoparticles are composed of mesoporous silica, calcium phosphate, chitosan, cationic polymers, and magnetic nanoparticles [ 32 ]. Recently, graphene oxide-polyethylenimine complexes have been reported to be an efficient and safe system for mRNA delivery for direct reprogramming of somatic cells to induced neurons [ 33 ]. Therefore, improvement of gene delivery efficiency using nanoparticles will be highly useful for direct conversion or reprogramming of somatic cells.

Biomaterials enhancing the therapeutic efficacy of stem cells

Tissues are composed of two components: cells and their surrounding extracellular matrix (ECM), which is known to play an important role in cell proliferation and differentiation. The main function of the ECM is maintaining cell growth and supplying essential components to cells [ 34 ]. ECM has been reported to create a framework for cell growth and to efficiently provide the nutrients or growth factors needed for cells [ 35 ]. It is difficult to naturally repair a large-size tissue defect by supplying cells to the injured sites, since not only the cells, but also the ECM are lost. Therefore, to promote tissue regeneration, it is necessary to make an artificial ECM environment for transplanted cells, and biomaterials are useful substitutes for ECM, and are also useful in cell therapy. The biomaterial scaffold should be porous for infiltration by cells into scaffolds, and for the supply of oxygen and nutrients to cells. In addition, the scaffold should be biodegradable for proper replacement of damaged tissues with the transplanted cells [ 36 ].

In terms of biomaterials, a variety of synthetic and natural materials have been developed. In particular, biodegradable polymers, such as collagen, gelatin, fibrin, hyaluronic acid, and poly(lactic-co-glycolic acid), are highly useful for tissue engineering [ 37 ]. The combination of these scaffolds and stem cells was used for skin wound healing [ 38 ]. The osteogenic efficiency of MSCs was confirmed in duck’s foot-derived collagen/hydroxyapatite scaffolds [ 39 ]. In addition, the increase of chondrogenic differentiation of MSCs in 3D alginate hydrogels was experimentally confirmed [ 40 ]. Neural stem cells have been used for treatment of neurodegenerative disease or stroke in pre-clinical and clinical studies; however, differentiation of neural stem cells to functional neurons, reconnection with host neural cells, and correct transmission of nerve signals are still obstacles to overcome [ 41 ]. Therefore, to enhance the survival and differentiation potentials of transplanted stem cells, it is necessary to combine biomaterials with growth factors, cytokines, and cell adhesive substances (Fig. 2 ).

Stem cell engineering strategy

3D bioprinting for tissue engineering

Biomaterial scaffolds can be used as structural components for different parts of tissues, such as blood vessels, skin, and corneal tissues [ 42 , 43 ]. Making 3D scaffolds and culturing stem cells on them improves the regenerative activity of stem cells for damaged bone and cartilage. Most tissues are composed of different cell types and multi-layered structures. Therefore, multi-layered 3D scaffolds are needed for construction of engineered tissues using stem cells. Currently, 3D bioprinting has drawn attention in the field of biotechnology for producing multi-layered structure. Since the first technology for 3D bioprinting cells had been reported, there have been great advances in 3D bioprinting-based tissue engineering [ 44 ]. Using 3D bioprinting, various cell types can be positioned in specific locations in multi-layered structures for constructing different tissues or organs (Fig. 3 ) [ 45 ]. Bioprinting technologies include inkjet [ 46 ] and laser deposition [ 47 ].

3D bioprinting of stem cells

In using inkjet printer technology, however, since the cells are printed in the same manner as a commercial printer, various problems arise. For example, in order to print stem cells through an inkjet printer, the material that is added to the cells must be in a liquid form and, subsequently, have a 3D structure after injection [ 48 ]. However, employing crosslinking agents to form 3D structures can impair cellular viability [ 49 ]. Despite these drawbacks, remarkable advances have been made due to the advantage of 3D printing cells being possible with slight modifications to commercial inkjet printers on the market [ 50 , 51 , 52 , 53 , 54 ]. Just as laser printers have become popular, laser printers for 3D bioprinting have also been developed. Unlike inkjet printers, laser printers do not apply physical stresses and do not require additives to maintain a liquid form. The viability of cells is higher than 95% after being printed, and apoptosis and cell proliferation are not affected [ 55 ].

For 3D bioprinting, bioinks are needed for printing of stem cells into 3D structures, and hydrogels are widely used as bioinks. Each bioink has its own characteristics and is used for specific purposes [ 56 ]. Natural bioinks include alginate, gelatin, collagen I, and fibrin; synthetic bioinks include polyethylene glycol and pluronic gels [ 57 ]. These materials have chemical and physical properties appropriate for bioink, and they serve as scaffolds, similar to those of the ECM [ 58 ]. In order to mimic the ECM in vivo, de-cellularized extracellular matrix (dECM) scaffold has been developed. dECM is obtained by processing original tissues with chemicals, or using enzymatic methods to remove cellular components [ 59 ]. Therefore, dECM is highly useful for 3D bioprinting of stem cells, or their differentiated progeny cells.

In the regeneration of thick tissues, not only the regeneration of the tissue itself, but also the regeneration of blood vessels plays an important role in maintaining the viability of the tissue. Artificial blood vessels applied to the human body need to have various characteristics, such as elasticity, permeability, and biocompatibility comparable to the original vessels [ 60 ]. To control blood vessel fabrication, the printer should have sufficient resolution, and bioinks should not deform under the printing conditions [ 61 ]. In one study, treatment with angiogenin, a stimulator of angiogenesis, in a fibrin/bone powder scaffold enhanced angiogenesis and bone formation, compared to a control group [ 62 ]. Therefore, it is possible to add pro-angiogenic factors during 3D bioprinting to facilitate blood vessel formation in the 3D printed tissues.

Application of 3D bioprinting technology for tissue regeneration

Recently, application of digital light processing stereolithography 3D printing technology for production of biodegradable polymeric vascular grafts has been reported [ 63 ]. Vascular grafts formed by 3D printing of human umbilical vein cells with poly propylene fumarate were applied for surgical grafting in patients with cardiovascular defects, suggesting that 3D bioprinting is highly useful for production of patient-specific vascular grafts [ 63 ]. In addition, 3D printing is also used for bone regeneration. Printed calcium phosphate scaffold have been widely used for bone regeneration [ 64 ]. Transplantation of calcium phosphate scaffold has proved effective in multiple animal studies [ 65 ]. Methods for increasing the osteogenicity of stem cells by applying polydopamine have also been developed [ 66 ]. In addition, 3D printing can be applied for cartilage regeneration. In one study, nanofibrillated cellulose plus alginate were used as scaffolds for making ears formed with a 3D printer, and the survival rate of chondrocytes in the scaffolds after transplantation was 73 to 86% [ 67 ]. In the case of bone and cartilage tissues, the size and shape of defects that occur in individual patients can be varied, therefore, 3D bioprinting technology may be highly useful for repair of damaged skeletal tissues [ 68 ].

Skin is the largest organ of the body, protecting the internal organs from external environments, retaining fluid, and acting as a sensory organ [ 69 ]. Thus, regeneration of skin wounds is important for not only cosmetic purposes but also restoration of physiologic function. In a clinical trial of treatment of burns, ulcers and other non-healing chronic wounds, stem cells have been proven to be an effective therapy for most patients [ 70 ]. In the case of burns or other large skin wounds, a method of transplanting through artificial skin fabricated out of polymers or human skin is widely used nowadays [ 71 ]. Although artificial skin substitutes for wound healing are commercially available, they have disadvantages such as a lack of viability, difficulty in reforming shape, and high costs [ 72 ]. It has been reported that skin-derived dECM bioinks can used to compensate for the rapid degradation and high contraction trends of traditional bioinks using conventional collagen. A printed mixture of adipose tissue-derived MSCs and endothelial progenitor cells with the skin-derived dECM for production of pre-vascularized skin grafts effectively accelerates cutaneous wound healing in animal models [ 73 ].

Conclusions

Most therapies or treatments eventually aim to enhance tissue regeneration, and stem cell engineering has opened a new path to regenerative medicine. In this paper, we reviewed the current status of stem cell technologies, biomedical engineering, and nanotechnology for tissue regeneration. Biomedical engineering and nanotechnology will be helpful for overcoming the shortcomings of stem cell therapeutics by supporting stem cells to grow to an appropriate concentration, offering homogeneity, and resulting in proliferation at the desired location. However, biomaterials may cause toxicity when applied to the human body; hence, several methods have been developed to increase the biocompatibility of biomaterials. Tissue engineering can be applied for construction of various tissues, such as blood vessels, nervous tissue, skin, and bone. For stem cell engineering, several techniques should be developed involving new materials, new structures, and novel surface modifications of biomaterials; in addition, a deeper understanding of the interactions between cells and biomaterials will be needed.

Abbreviations

Bone morphogenic proteins

De-cellularized extracellular matrix

Extracellular matrix

Mesenchymal stem cells

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Seong Gyu Kwon, Yang Woo Kwon, Tae Wook Lee, Gyu Tae Park & Jae Ho Kim

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Kwon, S.G., Kwon, Y.W., Lee, T.W. et al. Recent advances in stem cell therapeutics and tissue engineering strategies. Biomater Res 22 , 36 (2018). https://doi.org/10.1186/s40824-018-0148-4

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The impact of induced pluripotent stem cells in animal conservation

Published: 16 January 2024
Volume 48 , pages 649–663, ( 2024 )

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Yurou Wu 1 ,
Chengwei Wang 1 ,
Xinyun Fan 1 ,
Yuxiao Ma 2 ,
Zibo Liu 1 ,
Chongyang Shen 3 &
Chunjie Wu 4 , 5

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It is widely acknowledged that we are currently facing a critical tipping point with regards to global extinction, with human activities driving us perilously close to the brink of a devastating sixth mass extinction. As a promising option for safeguarding endangered species, induced pluripotent stem cells (iPSCs) hold great potential to aid in the preservation of threatened animal populations. For endangered species, such as the northern white rhinoceros ( Ceratotherium simum cottoni ), supply of embryos is often limited. After the death of the last male in 2019, only two females remained in the world. IPSC technology offers novel approaches and techniques for obtaining pluripotent stem cells (PSCs) from rare and endangered animal species. Successful generation of iPSCs circumvents several bottlenecks that impede the development of PSCs, including the challenges associated with establishing embryonic stem cells, limited embryo sources and immune rejection following embryo transfer. To provide more opportunities and room for growth in our work on animal welfare, in this paper we will focus on the progress made with iPSC lines derived from endangered and extinct species, exploring their potential applications and limitations in animal welfare research.

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Stem cells on regenerative and reproductive science in domestic animals

Naira Caroline Godoy Pieri, Aline Fernanda de Souza, … Fabiana Fernandes Bressan

Somatic Cells, Stem Cells, and Induced Pluripotent Stem Cells: How Do They Now Contribute to Conservation?

The use of induced pluripotent stem cells in domestic animals: a narrative review

Rachel A. Scarfone, Samantha M. Pena, … Thomas G. Koch

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This work was supported by the National Natural Science Fund of China (No. 82174226), the Tianfu laboratory transfer payment project (No. 2021ZYCD012).

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Wu, Y., Wang, C., Fan, X. et al. The impact of induced pluripotent stem cells in animal conservation. Vet Res Commun 48 , 649–663 (2024). https://doi.org/10.1007/s11259-024-10294-3

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Study documents safety, improvements from stem cell therapy after spinal cord injury

Susan Barber Lindquist

Stem cells' mechanism of action not fully understood

In the multidisciplinary clinical trial, participants had spinal cord injuries from motor vehicle accidents, falls and other causes. Six had neck injuries; four had back injuries. Participants ranged in age from 18 to 65.

Participants' stem cells were collected by taking a small amount of fat from a 1- to 2-inch incision in the abdomen or thigh. Over four weeks, the cells were expanded in the laboratory to 100 million cells and then injected into the patients' lumbar spine in the lower back. Over two years, each study participant was evaluated at Mayo Clinic 10 times.

Although it is understood that stem cells move toward areas of inflammation — in this case the location of the spinal cord injury — the cells' mechanism of interacting with the spinal cord is not fully understood, Dr. Bydon says. As part of the study, researchers analyzed changes in participants' MRIs and cerebrospinal fluid as well as in responses to pain, pressure and other sensation. The investigators are looking for clues to identify injury processes at a cellular level and avenues for potential regeneration and healing.

The spinal cord has limited ability to repair its cells or make new ones. Patients typically experience most of their recovery in the first six to 12 months after injuries occur. Improvement generally stops 12 to 24 months after injury. In the study, one patient with a cervical spine injury of the neck received stem cells 22 months after injury and improved one level on the ASIA scale after treatment.

Two of three patients with complete injuries of the thoracic spine — meaning they had no feeling or movement below their injury between the base of the neck and mid-back — moved up two ASIA levels after treatment. Each regained some sensation and some control of movement below the level of injury. Based on researchers' understanding of traumatic thoracic spinal cord injury, only 5% of people with a complete injury would be expected to regain any feeling or movement.

"In spinal cord injury, even a mild improvement can make a significant difference in that patient's quality of life," Dr. Bydon says.

Research continues into stem cells for spinal cord injuries

Stem cells are used mainly in research in the U.S., and fat-derived stem cell treatment for spinal cord injury is considered experimental by the Food and Drug Administration.

Between 250,000 and 500,000 people worldwide suffer a spinal cord injury each year, according to the World Health Organization .

An important next step is assessing the effectiveness of stem cell therapies and subsets of patients who would most benefit, Dr. Bydon says. Research is continuing with a larger, controlled trial that randomly assigns patients to receive either the stem cell treatment or a placebo without stem cells.

"For years, treatment of spinal cord injury has been limited to supportive care, more specifically stabilization surgery and physical therapy," Dr. Bydon says. "Many historical textbooks state that this condition does not improve. In recent years, we have seen findings from the medical and scientific community that challenge prior assumptions. This research is a step forward toward the ultimate goal of improving treatments for patients."

Dr. Bydon is the Charles B. and Ann L. Johnson Professor of Neurosurgery. This research was made possible with support from Leonard A. Lauder, C and A Johnson Family Foundation, The Park Foundation, Sanger Family Foundation, Eileen R.B. and Steve D. Scheel, Schultz Family Foundation, and other generous Mayo Clinic benefactors. The research is funded in part by a Mayo Clinic Transform the Practice grant.

Review the study for a complete list of authors and funding.

About Mayo Clinic Mayo Clinic is a nonprofit organization committed to innovation in clinical practice, education and research, and providing compassion, expertise and answers to everyone who needs healing. Visit the Mayo Clinic News Network for additional Mayo Clinic news.

Media contact:

Susan Barber Lindquist, Mayo Clinic Communications, [email protected]
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Study uncovers multiple lineages of stem cells contributing to neuron production

by Elena Garrido, Miguel Hernandez University of Elche

The development of the cerebral cortex largely depends on the stem cells responsible for generating neurons, known as radial glial cells. Until now, it was believed that these stem cells generated neurons following a simple process, that is, a single cell lineage.

However, a study led by the Neurogenesis and cortical expansion laboratory, headed by researcher Víctor Borrell at the Institute for Neurosciences (IN), a joint center of the Spanish National Research Council (CSIC) and the Miguel Hernández University (UMH) of Elche, has discovered not only that there are many more types of radial glial cells than previously thought, but also that there are at least three different processes of neurogenesis that occur in parallel in the same brain areas and at the same moment of development.

The results of this work, published in the journal Science Advances , reveal the complexity of neurogenesis through the involvement of parallel lineages. "We have discovered that there are several alternative routes to generate neurons and that all the routes work at the same time, although we have also seen that the final result is always a neuron with similar characteristics and functions at that stage of development," explains Borrell.

Furthermore, researchers find evidence that the existence of parallel lineages is related to the folding of the cerebral cortex. "A fundamental aspect in this sense is that the 'routes' to form neurons work at the same time and in the same place, but not in the same quantity throughout the cortex, being different between gyrus and sulcus," says the article's first author, Lucía del Valle Antón.

To understand this link, researchers have studied the formation of neurons in regions that will undoubtedly give rise to a gyrus and a sulcus in the ferret brain, while, by using public databases, they have also been able to analyze it in human and mouse brains.

During the development of the study, in which the researcher Juan Antonio Moreno Bravo, who directs the Development, Wiring, and Function of Cerebellar Circuits laboratory, also participated, the experts observed that, although the three lineages are functioning in both gyrus and sulcus zones, different processes predominate depending on the location.

"At first, the cortex is smooth, but there is an area that will grow a lot, and as it grows, it will end up forming a gyrus. Meanwhile, next to it, other areas will grow less and will remain sunken, forming a sulcus," says Borrell. "The first difference between a gyrus and a sulcus is how much it grows, and this is related to how many neurons will be born in that place. For example, in the sulcus, what we find is that of these three 'routes,' the one that generates fewer neurons predominates, while in the gyrus, the opposite will happen."

Understanding the existence of these new types of stem cells , which possess a high capacity for division, along with the various mechanisms for generating neurons in parallel, enables us to comprehend the processes that lead to the enlargement of the human cerebral cortex compared to other species.

This research has allowed scientists to explore, with unprecedented detail, the genes expressed by neurons in both the gyrus and the sulcus. Borrell explains, "We aimed to observe which of all the cells we investigated express genes known to be mutated in human malformations. We verified that not all these cells express the genes responsible for these brain malformations. We observed that they are mainly expressed by the newborn neurons, rather than the progenitors."

Along these lines, the researcher highlights that, despite having the same functions at a global level, the neurons that are born in the gyrus express genes that are essential for the human cortex to have gyri. This indicates that, when patients have malformations because their brain lacks gyri, the defects occur specifically in the neurons of the gyrus and not in those of the sulcus.

International collaboration

In this study, which involved collaboration with researchers from the ISF Stem Cell Research Institute (Helmholtz Zentrum) and the Max Planck Institute for Biological Intelligence, both located in Munich (Germany), the researchers based their results on the sequencing of individual cells at the transcriptomics level, a technique that enables us to identify all the genes that are expressed in each of the cells.

Scientists analyzed thousands of cells using informatics tools to determine the genetic trajectory of these cells and their respective lineages. Upon investigating and validating the lineage data across the three species, they observed that in the human brain, these three parallel lineages also occur, similar to what is observed in ferrets.

However, in the case of mice, analyses conducted have observed only a single predominant route in the creation of neurons. Future research will be necessary to determine whether mice lost these lineages due to evolution or if, on the contrary, these "routes" are still present but in such small proportions that they are undetectable with current tools.

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Revolutionizing Medicine: the Potential of Stem Cell Therapy

This essay about the transformative potential of stem cell therapy explores its profound impact on the future of medicine. Stem cells, with their remarkable ability to regenerate and repair damaged tissues, offer hope for conditions ranging from neurodegenerative disorders to heart disease. By addressing the root causes of diseases, stem cell therapy transcends conventional treatments, envisioning a future where healing is more than just symptom management. Despite the challenges of scientific, regulatory, and ethical complexities, collaborative efforts are driving progress towards unlocking the full potential of stem cell therapy. As we stand on the brink of a new era in healthcare, the promise of stem cell therapy to revolutionize medicine shines bright, offering a glimpse into a future where diseases are conquered, and hope prevails.

How it works

In the ever-evolving narrative of medical progress, few chapters resonate as profoundly as the saga of stem cell therapy. Embarking on a journey fraught with promise and potential, stem cell therapy heralds a seismic shift in the way we approach healing, offering a tantalizing glimpse into a future where the specter of debilitating diseases is relegated to the annals of history.

At its core, stem cell therapy hinges on the extraordinary versatility of stem cells – nature’s master architects endowed with the remarkable ability to metamorphose into an array of specialized cell types within the human body.

With their intrinsic capacity for regeneration, repair, and replacement of damaged tissues, stem cells emerge as the vanguards of a new era in medicine, poised to rewrite the script for conditions ranging from neurodegenerative disorders like Parkinson’s and Alzheimer’s to the scourge of heart disease, spinal cord injuries, and diabetes.

What sets stem cell therapy apart is its audacious aim to confront diseases at their very roots, venturing beyond mere symptom management to address the underlying pathology with surgical precision. Unlike conventional treatments that often serve as transient respite, stem cell therapy envisions a future where the orchestration of cellular rejuvenation and restoration becomes the hallmark of healing.

The versatility of stem cells knows no bounds, with diverse sources offering a veritable treasure trove of therapeutic potential. From the pluripotent prowess of embryonic stem cells, derived from the earliest stages of embryonic development, to the ethically uncomplicated abundance of adult stem cells found within tissues like bone marrow, adipose tissue, and umbilical cord blood, the arsenal of stem cell sources spans the spectrum of ethical and scientific considerations.

Already, the reverberations of stem cell therapy are reverent in clinical arenas, where a constellation of success stories illuminates its transformative impact. In conditions like leukemia and lymphoma, bone marrow transplants, a stalwart of stem cell therapy, emerge as harbingers of hope, effecting a cellular renaissance that vanquishes cancerous cells and restores hematopoietic harmony. Similarly, in orthopedic realms, stem cell injections emerge as stalwart allies in the crusade against degenerative joint diseases and tendon injuries, fostering tissue regeneration and assuaging the ravages of inflammation.

Yet, the journey towards the widespread adoption of stem cell therapy is fraught with obstacles that demand innovative solutions. Scientific enigmas, regulatory labyrinths, ethical quandaries, and economic exigencies converge to impede progress on this frontier. Research endeavors persevere in unraveling the intricacies of stem cell biology, endeavoring to optimize protocols for cellular manipulation, differentiation, and delivery while upholding the precepts of safety and efficacy.

Furthermore, regulatory frameworks must evolve in consonance with scientific advancements, striking a delicate equilibrium between fostering innovation and safeguarding patient welfare. Navigating the intricate terrain of regulatory oversight is imperative to unlocking the transformative potential of stem cell therapy and ensuring equitable access to its benefits.

Despite the formidable challenges that lie ahead, the momentum behind stem cell therapy continues to burgeon, propelled by a collective determination to reshape the contours of healthcare. Through collaborative synergy among scientists, clinicians, policymakers, and industry stakeholders, the barriers to progress are being dismantled, paving the way for a future where the healing potential of stem cells is fully realized.

As we stand on the precipice of a new dawn in medicine, the promise of stem cell therapy to revolutionize healthcare is as compelling as it is inexorable. From rejuvenating damaged tissues to confronting once-intractable diseases, the transformative power of stem cells beckons us toward a future where the boundaries of healing are redefined, and hope springs eternal.

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Published: 20 August 2022

Scaffold-based delivery of mesenchymal stromal cells to diabetic wounds

Shanshan Du 1 , 2 ,
Dimitrios I. Zeugolis 2 , 3 , 4 &
Timothy O’Brien 1 , 2

Stem Cell Research & Therapy volume 13 , Article number: 426 ( 2022 ) Cite this article

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Foot ulceration is a major complication of diabetes mellitus, which results in significant human suffering and a major burden on healthcare systems. The cause of impaired wound healing in diabetic patients is multifactorial with contributions from hyperglycaemia, impaired vascularization and neuropathy. Patients with non-healing diabetic ulcers may require amputation, creating an urgent need for new reparative treatments. Delivery of stem cells may be a promising approach to enhance wound healing because of their paracrine properties, including the secretion of angiogenic, immunomodulatory and anti-inflammatory factors. While a number of different cell types have been studied, the therapeutic use of mesenchymal stromal cells (MSCs) has been widely reported to improve delayed wound healing. However, topical administration of MSCs via direct injection has several disadvantages, including low cell viability and poor cell localization at the wound bed. To this end, various biomaterial conformations have emerged as MSC delivery vehicles to enhance cell viability and persistence at the site of implantation. This paper discusses biomaterial-based MSCs therapies in diabetic wound healing and highlights the low conversion rate to clinical trials and commercially available therapeutic products.

Introduction

Diabetic foot ulcers are the main cause of amputation in patients with diabetes mellitus, resulting in high healthcare costs, reduced quality of life and increased mortality. The 10th edition of the International Diabetes Federation Atlas has reported that the number of patients suffering from diabetes mellitus in 2021 was 536.6 million, and there will be approximately 783.2 million adults with diabetes by 2045 [ 1 ]. The global health expenditure on diabetes mellitus is estimated to reach US$ 1,054 billion by 2045, increasing 9.1% from US$ 966 billion in 2021 [ 2 ]. The global epidemiology of diabetic foot ulcers has been reported to have a prevalence of 6.3%, which was higher in males than females, and in patients with type 2 diabetes mellitus than in those with type 1 (6.4% vs 5.5%) [ 3 ]. From a global perspective, the prevalence of diabetic foot ulcers in North America, Asia, Europe, Africa and Oceania was 13.0%, 5.5%, 5.1%, 7.2% and 3.0%, respectively [ 3 ]. It is estimated that approximately 25% of patients with diabetes mellitus will develop a foot ulcer during their lifetime [ 4 ], and around 14–24% of patients with foot ulcers will ultimately require an amputation [ 5 ]. In the UK, the number of patients with chronic wounds was estimated to be 2.1 million, increasing at the rate of 12% annually with annual health care expenditure of approximately £5 billion [ 6 ]. In the United States, approximately 6.5 million people experience diabetic foot ulcers with the cost for wound care management in the range of US$ 28.1 to US$ 96.8 billion [ 7 , 8 ]. Therefore, diabetes mellitus and the complication of foot ulceration have major human, societal and economic costs.

To date, numerous approaches have been developed for chronic wound management and treatment, such as gene therapy, growth factor therapy, stem cell therapy, and use of biomaterials. Current treatment methods for diabetic wound healing are not always effective [ 9 , 10 ]. The basic care of neuropathic foot ulcers consists of wound debridement and off weight bearing, while ischemic ulcers require revascularization. It has been well-established in the literature that MSCs secrete growth factors, cytokines, and chemokines which may contribute to the therapeutic potential in the context of diabetic wound healing [ 11 , 12 , 13 ]. In addition, MSCs impact each phase of the wound healing process via modulation of immune responses, and promotion of angiogenesis and tissue remodelling [ 13 , 14 ].

Current cell-based treatments are mainly focused on cell injections either delivered systemically or intradermally. MSCs administrated via the systemic route have shown that the majority of cells entrap in the lung, and only a small portion of cells travel to the wound site [ 15 ], whereas intradermally injecting MSCs into the wound edges significantly improved the wound healing process [ 16 ]. However, the therapeutic effect of MSCs can still be compromised by poor cell localisation and impaired cell viability at the site of injury [ 17 ]. To overcome these problems, the use of scaffolds has been advocated as a means to increase cell viability and retention at the wound bed and provide a three-dimensional structure for cell migration, proliferation and differentiation [ 18 ]. Herein, we summarize the underlying mechanism of MSC mediated diabetic wound healing, along with significant advances and shortfalls of biomaterial-based MSC therapies in diabetic wound healing in preclinical and clinical settings.

MSC mediated diabetic wound healing

Normal wound healing progresses through four overlapping phases: haemostasis, inflammation, proliferation, and remodelling. Diabetic wounds are characterised by a delayed inflammatory phase, and therefore take a long time to heal [ 19 ]. In most patients, the underlying etiology of diabetic wounds is mainly due to a combination of factors such as peripheral neuropathy, peripheral artery disease and impaired immune response [ 20 ]. Neuropathy results in impaired sensory, motor, and autonomic nerves leading to inability to detect external stimuli such as pressure, heat and the creation of wounds [ 21 , 22 ]. Peripheral artery disease results in ischemia and microcirculatory dysfunction, leading to a decrease in local angiogenesis [ 23 ]. Some patients also show a reduced immune response to infections which inhibits wound healing [ 24 ]. Collectively, multiple factors contribute to the prolonged inflammatory phase, including the existence of persistent infection, the infiltration of inflammatory cells (neutrophils, monocytes/macrophages, mast cells and T cells), the excessive levels of proinflammatory cytokines, chemokines, proteases, reactive oxygen species and senescent cells, as well as the release of ECM degradation enzymes such as matrix metalloproteases and collagenases [ 25 , 26 ]. The underlying pathophysiological mechanisms relate to increased oxidative stress, diminished cell recruitment and proliferation, deficiency of growth factors, impaired formation of collagen matrix, and, most importantly, impaired angiogenesis and/or neovascularization [ 23 , 27 , 28 , 29 , 30 , 31 ].

In the quest for the ideal treatment, the use of MSCs has been advocated, considering their role in wound healing and their overall self-renewable, immunomodulatory, anti-inflammatory, anti-fibrotic, angiogenic and therapeutic capacities [ 32 , 33 , 34 ]. The main molecular mechanism in MSC-mediated diabetic wound healing is that MSCs secrete angiogenic growth factors, immunomodulatory factors, remodelling molecules, and extracellular vesicles (EVs) to enhance re-epithelialization, granulation tissue formation, and neovascularization in the diabetic wound bed [ 35 ]. Rat adipose derived MSCs (AD-MSCs) were found to secrete angiogenic factors (vascular endothelial growth factor (VEGF), hepatocyte growth factor (HGF), and basic fibroblast growth factor (bFGF)) in vitro and in vivo, resulting in an increased neovascularization and enhanced wound closure in diabetic rat model [ 36 ]. MSCs can migrate and home to the wound area and adhere to endothelial cells via interferon gamma, tumour necrosis factor-α (TNF-α), C–C chemokine receptor type 7, intercellular adhesion molecule-1(ICAM-1), vascular cell adhesion molecule 1, and Akt-dependent mechanisms [ 37 , 38 , 39 ]. At the wound area, MSCs stimulate neovascularization, through interaction with VEGF, endothelial nitric oxide synthase and hypoxia-inducible factor (HIF) pathways [ 38 ], and immunomodulation, via interaction with T and B cells, macrophages and natural killer cells [ 40 ]. Intradermally injecting MSCs around diabetic wounds accelerated the wound closure, re-epithelialization and granulation tissue formation via secretion of chemokines, inflammatory cytokines and immune factors including TNF-α, interleukin (IL)-1, IL-6, IL-8, MCP-1, PEG2 and IL-10 [ 41 , 42 , 43 , 44 ]. MSCs inhibit the expression of matrix metallopeptidase(MMP)-1 and upregulate MMP-9 to suppress the degradation of collagen matrix and facilitate fibroblast and keratinocyte proliferation and migration across the wound bed [ 45 ]. EVs secreted by MSCs, containing proteins, microRNAs, coding RNAs and non-coding RNAs, and mitochondria, demonstrated a positive effect on diabetic wound healing as well. MSC-derived EVs containing long noncoding RNA H19 stimulate diabetic wound healing process through suppressing the apoptosis and inflammation of fibroblasts via miR-152-3p-mediated PTEN axis [ 46 ]. EVs derived from MSCs containing miR-126 activate the PI3K/AKT signalling pathway via downregulating PTEN, resulting in enhanced wound healing and angiogenesis in diabetic rat wounds [ 47 ]. EVs derived from MSCs containing either let-7b [ 48 ] or miR-211-3p [ 49 ], target TRL4/NF-κB/STAT3/AKT pathway and AKT/eNOS pathway, respectively, modulating immune response, inflammation and angiogenesis in diabetic preclinical wound models.

Although MSCs have been shown to improve wound healing, their short time in the wound bed prevents the full realization of their therapeutic potential and has triggered investigations of the optimal MSC carrier system (Fig. 1 , Table 1 ).

Summarized representations of various scaffolds used for MSC delivery. Enhanced delivery of MSC can be achieved using scaffolds and grafts that mimic or retain the architecture of natural human tissue, providing a favourable microenvironment for MSCs to attach, proliferate, and retain their secretome, as well as guide the host cell migration. The secretome of MSCs stimulate the infiltration and migration of immune cells (macrophages, lymphocytes, and neutrophil) that will modulate the inflammation and immune response in the wound bed, thus promoting angiogenesis and improving wound healing. From left to right, we depicted the main cell carriers used to delivery MSCs in diabetic wound healing studies. Hydrogel scaffolds hold a high fraction of water within its structure; sponge scaffolds exhibit highly uniform interconnected pore network; fibrous scaffolds consist of fibres at microscale or nanoscale level; and decellularized grafts retain their native ECM elements and anatomical structure. (Created in BioRender.com)

Hydrogel scaffolds for MSC delivery in diabetic models

Hydrogels are three-dimensional networks comprised of natural, synthetic or combinations of polymers that have the ability to swell and hold a significant fraction of water within their structure (Fig. 1 ). Hydrogels have received considerable attention in therapeutic approaches to wound healing, due to their ability to maintain cell viability at the implantation site and flexibility of fabrication [ 50 , 51 ]. The naturally derived hydrogels have shown several advantages: biocompatibility, biodegradability, intrinsic cellular interactions, and structural similarity to the natural human tissue [ 52 ]. In contrast, the limitations of natural hydrogels include a narrow range of mechanical properties and batch variability [ 53 ]. Therefore, natural and synthetic hydrogels are often combined to create composite hydrogels with controlled structure and function [ 54 ]. Composite hydrogel scaffold designs have attracted significant attention since their properties of being able to be engineered with controllable shape, size, surface competence, biodegradation and biocompatibility, which suit the mechanical and biomedical requirements for wound healing and skin regeneration [ 55 ]. Several hydrogel systems have been assessed as MSC carriers in diabetic wound healing models (Table 2 ). In spite of this extensive literature, which is reviewed here, progression to the clinic is limited. As clinical translation is the goal of preclinical research, in this section, studies conducted using MSCs from different species were summarised separately to demonstrate the current research status based on the species of origin of the transplanted cells.

Hydrogel scaffolds for mouse-MSC delivery

A few studies investigated the therapeutic effect of mouse-MSCs delivered via different composited hydrogels to diabetic mouse wound models. It should be noted that delivery of mouse cells to mice will avoid any potential xenogeneic response when human derived cells are used. However, from a translational perspective this may create problems as the final product will use human cells which will not then be studied. There will be a need to show that the animal cells are identical to the human cells. Collagen is the most abundant protein in skin and has been considered as the first choice cell delivery platform for diabetic wound healing. Mouse bone marrow-derived MSCs (BM-MSCs) and AD-MSCs delivered with a type I rat tail collagen hydrogel enhanced wound healing in a diabetic mouse model by increasing growth factor expression (e.g. VEGF), and recruiting macrophages to modulate immune and inflammatory responses in the wound bed [ 56 , 57 ]. The wound closure rate was significantly increased compared with the collagen alone group, suggesting that collagen hydrogel successfully delivered MSCs to the wound bed and enhanced the therapeutic outcome. Gelatin is a matrix metalloproteinase sensitive biodegradable biomacromolecule that is derived from collagen. When gelatin was combined with poly(ethylene glycol) (PEG), the hydrogel demonstrated a tuneable degradation speed depending on cell number and material concentration; when the right conditions were defined, the degradation process took place in parallel with the wound healing process [ 58 ]. Mouse AD-MSCs delivered by a gelatin hydrogel crosslinked by hyperbranched poly(ethylene glycol) diacrylate (PEGDA), demonstrated excellent cell attachment and maintained cell proliferation, cell viability and metabolic activity for 3 weeks. After injecting the AD-MSC-hydrogel on the wound surface of db/db diabetic mouse, cell retention in the wound bed was significantly improved, resulting in enhanced wound closure and neovascularization and reduced inflammation compared with no-treatment, cell alone and hydrogel alone controls [ 59 ]. In addition, mouse BM-MSCs were delivered via a biodegradable n-isopropylacrylamide-based, thermosensitive hydrogel to treat wounds in a db/db mouse model, resulting in enhanced extracellular matrix (ECM) deposition, neovascularization, re-epithelialization and granulation tissue formation via modulation of the polarization of M1 and M2 macrophages in the wound bed compared with no-treatment and hydrogel alone controls [ 60 ]. This thermosensitive hydrogel has been shown to promote the secretion of transforming growth factor-β (TGFβ)-1 and bFGF in BM-MSCs in vitro, which maybe the underlying mechanism of MSCs promoting diabetic wound healing.

Hydrogel scaffolds for rat-MSC delivery

Pluronic F-127, a synthetic and biocompatible hydrogel, has been extensively investigated in the applications of drug delivery and controlled release in the past decade [ 61 ]. The unique characteristic of thermosensitivity, enables Pluronic F-127 hydrogel to easily encapsulate large numbers of cells and be delivered to the wound bed. Rat AD-MSCs encapsulated in Pluronic F-127 hydrogel significantly accelerated wound closure by enhanced angiogenesis and cell proliferation at the wound site in a streptozotocin (STZ) induced diabetic rat model [ 62 ]. Compared to no treatment, cell alone and hydrogel alone control groups, relative mRNA expression levels of key angiogenic (VEGF), and wound healing growth factors (TGF-β1) were upregulated in the MSC-hydrogel treated wounds, suggesting that MSC-hydrogel engraftment promoted wound healing via paracrine mechanisms. Rat AD-MSCs engrafted in silk-fibroin/chitosan hydrogel significantly improved re-epithelialization and granulation tissue formulation and capillary formation in diabetic rat wound bed after 7 days of treatment compared with the no-treatment and scaffold alone groups [ 63 ]. After 14 days of hydrogel-MSC treatment, the protein expression level of epidermal growth factor (EGF), TGF-β and VEGF in the wound bed were significantly increased compared with the non-treatment and scaffold alone groups. In addition, rat BM-MSCs delivered by a hydrogel consist of N -chitosan and HA to the wound bed of diabetic rats, inhibited chronic inflammation, promoted granulation tissue formation, collagen deposition and nucleated cell proliferation, and stimulated neovascularization, which resulted in enhanced diabetic wound healing. In vitro assessment revealed this HA-based hydrogel promoted the secretion of TGF-β1, VEGF and bFGF of BM-MSC [ 64 ].

Hydrogel scaffold for rabbit-MSC delivery and others

Rabbit BM-MSCs delivered by a nitric-oxide-releasing hydrogel significantly improved wound healing rate, re-epithelialization, collagen deposition and upregulated the gene-expression of VEGF and stromal cell-derived factor(SDF)-1α in the wound bed of a diabetic rabbit model compared with no-treatment, cell alone and hydrogel alone controls [ 65 ].

In another study, AD-MSCs (unknown species) delivered by hyaluronic acid (HA) based composite hydrogel to diabetic rat wound, promoted the reconstruction of blood vessels, hair follicles and dermal collagen matrix, via the maintenance of stemness of MSC and upregulation of the gene expression of HIF-1 α and connexin 43 in the wound bed compared with no-treatment, MSC alone and hydrogel alone controls [ 66 , 67 ]. However, it is important to acknowledge the importance of specifying the species of MSC used in pre-clinical research in order to understand the full implications of the results. Moreover, this is key to consider the potential translation in clinical settings from early stages of experimental design and product development.

Hydrogel scaffold for human-MSC delivery

In terms of hydrogel mediated human MSC delivery, subcutaneous injection of human AD-MSC micro-hydrogel prepared by HA improved wound healing in db/db mouse and resulted in faster wound epithelialization with thicker dermis formation compared with no-treatment, and hydrogel alone groups [ 68 ]. In this AD-MSC-hydrogel construct, the expression of stemness markers (NANOG, OCT3/4, SOX-2 and SSEA-3) at the protein level were significantly up-regulated compared with cells in monolayer culture, suggesting that this hydrogel mimicked a physiological microenvironment that promoted cell growth and induced a stemness-like phenotype [ 68 , 69 ]. Human AD-MSCs have also been delivered through a combination of HA and gellan gum hydrogel for the treatment of diabetic mouse wounds. In this study, an improved impact on the neovascularization of diabetic wounds was observed and the epidermis of the healed diabetic wound was shown to be thicker and more differentiated than no-treatment control [ 70 ]. Decellularized adipose matrix, after freeze-drying, digestion with pepsin and neutralization, can also serve as a hydrogel for human AD-MSC delivery [ 71 ]. This thermosensitive hydrogel presented similar structural and biochemical complexity of native ECM, supported human AD-MSCs survival and proliferation, increased the MSC paracrine secretion (HGF), eventually enhanced the wound closure and neovascularization compared to local injection of AD-MSCs in a diabetic mouse model. On the other hand, researchers have applied engineered VEGFA-hypersecreting human BM-MSCs to db/db mouse wound bed by either direct injection or embedding cells in HyStem®-HP hydrogel. The results showed that both cell delivery methods improved wound healing rate, with a significant difference observed from 7–9 days after treatment, and the cells delivered by the hydrogel group showed similar healing kinetics compared to the direct injection group [ 72 ]. Another study reported that encapsulating a mixture of human BM-MSCs and rat insulin secreting cells (ISCs) in a PEGDA hydrogel promoted diabetic wound healing almost 3 times faster than control group (14 vs. ~ 40 days), without intermediate scab or scar, through increased secretion of insulin, VEGF, TGF-β1 and the viability and function of MSC improved due to activation of the PI3K-Akt/PKB pathway [ 73 ]. This observation suggests that a combination of different cell types may further enhance the therapeutic effects in the diabetic wound.

Sponge scaffolds for MSC delivery in diabetic models

Sponge scaffolds are fabricated by natural or synthetic polymers via various techniques (e.g. porogen leaching, gas foaming and freeze-drying methods) and exhibit high porosity and a uniform interconnected pore network (Fig. 1 ) [ 74 , 75 ]. Sponge scaffolds for tissue engineering can be described using several criteria, including pore size, porosity, water uptake and retention capacity [ 76 ]. The major difference between sponge and hydrogel scaffolds is the fabrication method which results in a difference in the percentage of water content in the scaffold. Compared to hydrogel, the fabrication procedure of sponge scaffolds is time consuming, and the surface and structure require to be adjusted depending on cell type and host tissue. Sponge scaffolds hold several potential advantages for skin wound healing. The highly porous structure of sponge scaffolds mimics the architecture of ECM supporting cells to migrate to the site of the defect [ 77 ]. The water uptake and retention capacity of sponge scaffolds allows them to absorb the exudate in the wound bed and provides a favourable environment for cell migration and proliferation [ 78 ].

In terms of utilisation of sponge scaffolds in diabetic wound healing applications, collagen and chitosan-based sponge scaffolds are the most commonly used MSC carriers. O’Loughlin, et al. have developed a collagen sponge scaffold using a freeze-drying method. Compared to no-treatment control, the topical administration of allogeneic BM-MSCs through a collagen sponge scaffold augmented wound closure and increased angiogenesis after transplantation for 7 days in the diabetic rabbit wound [ 79 ]. A collagen-chitosan sponge scaffold was constructed using cross-linking and a freeze-drying method, resulting in a 100 μm network pore configuration and a suitable swelling ratio and appropriate biodegradability for BM-MSC delivery [ 80 ]. This sponge scaffold provided a microenvironment whereby hypoxia pre-treated rat BM-MSCs secreted higher levels of proangiogenic factors such as VEGF and platelet-derived growth factor (PDGF) and upregulated the expression of key transcription factors such as HIF-1α, while maintaining cell viability. Transplantation of this BM-MSC-scaffold construct to a STZ-induced diabetic rat wound model, resulted in improved wound closure, increased angiogenesis and decreased inflammation (enhanced gene and protein expression of anti-inflammatory cytokine IL-10 at 7 and 14 days) in the wound bed compared to scaffold alone group. In addition, researchers developed a chitosan-collagen scaffold containing simvastatin that exhibited high porosity (pore size in a range of 20–200 μm), suitable mechanical strength with similar elasticity as human skin (83.3 ± 34.9 MPa) [ 81 ] and a controlled release of simvastatin. Rat epidermal-derived MSCs delivered by this scaffold resulted in increased wound closure rate, promoted vascularization, enhanced viability and proliferation of MSCs in diabetic rat wound compared to no-treatment control and scaffold alone group [ 82 ]. In another study, sponge scaffold consisting of glycol chitosan and polyurethane delivering rat AD-MSCs to STZ-induced diabetic rat wound, and combined with acupuncture produced synergistic immunomodulatory effects, resulted in improved wound closure (90.34 ± 2.3%) and complete re-epithelialization in 8 days than AD-MSC alone group [ 83 ]. The secretion of cytokines SDF-1 and TGF β-1 were upregulated and proinflammatory cytokines TNF-α and IL-1β were downregulated in the wound bed after 8 days treatment. Furthermore, sponge scaffolds can also conjugate with growth factors as a cell delivery system. Chitosan-alginate sponge scaffolds conjugated with EGF delivering BALB/c mouse BM-MSCs, resulted in enhanced cell viability and expression of transcription factors associated with the maintenance of pluripotency and self-renewal (OCT3⁄4, SOX2, and Nanog) in vitro, and showed significant improvement of wound closure, by increasing granulation tissue formation, collagen deposition and angiogenesis in diabetic rat wound as compared to no-treatment control and MSC alone groups [ 84 ].

Fibrous scaffolds for MSC delivery in diabetic models

Fibrous scaffolds are mainly developed by an electrospinning method to create three-dimensional constructs consisting of fibres at microscale or nanoscale level to mimic the architecture of natural human tissue ( Fig. 1 ) [ 85 , 86 , 87 ]. Electrospinning is a technique that has been investigated for decades, by using electrostatic forces to produce continuous fibres from biocompatible materials [ 88 ]. The alignment of a fibrous scaffold can be random or aligned depending on the requirements for application. Other techniques, such as fibre bonding and needle punch, have also been used for fabrication of fibrous scaffolds [ 89 ]. Fibrous scaffolds have been employed in various tissue engineering fields, including bone, cartilage, skin, vascular and neural tissue engineering [ 90 ]. The high surface-area-to volume ratio of fibrous scaffolds allows cell adhesion, however small pore size may hinder cell migration and need to be adjusted based on cell type [ 91 ]. In recent years, there has been an increasing number of publications using fibrous scaffolds in wound healing applications due to their ability to serve as a structural template, improve cell–cell and cell–matrix interactions, and to direct cell behaviour and function (e.g. cell morphology, cell proliferation, differentiation) [ 77 , 90 ].

In terms of cell delivery, fibrous scaffolds have been used as MSC carriers for diabetic wound healing. Chen et al. have developed a three-dimensional scaffold using polycaprolactone, pluronic-F-127 and gelatin to deliver mouse BM-MSC. Compared with no-treatment and scaffold alone controls, this fibrous scaffold-MSC construct resulted in enhanced granulation tissue formation, angiogenesis and collagen deposition in the wound bed of diabetic mouse, through modulating the polarization of macrophages and expression of inflammatory cytokines [ 92 ]. This radially and vertically aligned fibrous scaffold has size and shape characteristics which can be tailored to be suitable for various wounds. In addition, a hybrid electrospinning nanofiber scaffold containing 80% polylactic acid, 10% silk and 10% collagen was developed as a cell carrier to deliver HO-1-overexpressing human BM-MSCs to the diabetic mouse wound bed, resulting in significantly enhanced angiogenesis and wound healing via Akt signalling pathways [ 93 ]. Researchers have also used this platform to deliver brain-derived neurotrophic factor activated human BM-MSCs to the wound bed in a diabetic mouse model. Significantly accelerated wound closure and enhanced blood vessel formation on the wound bed was observed with the underlying mechanism potentially related to milieu-dependent differentiation [ 94 ]. Moreover, a fibrous scaffold made of aloe vera and polycaprolactone was developed to deliver human umbilical cord-derived MSCs (UC-MSCs) or their conditioned medium to the db/db mouse wound bed, with both treatments showing rapid wound closure, re-epithelialization and increased number of sebaceous glands and hair follicles after transplantation to the wounds for 28 days, no significant difference was observed between the two treatments throughout the study period [ 95 ]. After both treatments the wound showed positive keratinocyte markers and increased cytokine expression of ICAM-1, tissue inhibitor matrix metalloproteinase 1 (TIMP-1), and VEGF-A at day 14 and 28. Furthermore, a silk fibroin (SF) scaffold delivering human AD-MSCs to a db/db mouse wound model, resulted in complete wound closure at 10 days versus 15–17 days for controls [ 96 ]. The same therapeutic effects were observed even after removing MSCs from the SF-MSC bio-complex, indicating that the MSC secretions stored in the scaffold play a key role in improving the wound healing process.

Decellularized grafts for MSC delivery in diabetic models

Decellularized grafts are mainly derived from tissues or organs through mechanical (freezing, force etc.), chemical (acid, Triton etc.) or enzymatic (trypsin, pepsin etc.) decellularization procedures to remove cellular components [ 97 ]. Commonly used tissue or organs include skin [ 98 ], Wharton's jelly [ 99 ] adipose tissue [ 100 ] and in vitro cultured cells [ 101 ]. Compared to other synthetic scaffolds, decellularized grafts are non-immunogenic and retain their native ECM elements (e.g. collagen, elastin, laminin and fibronectin), and anatomical structure (Fig. 1 ) [ 100 , 101 , 102 ]. These advantages are essential in identifying and developing scaffolds for implantation in diabetic wounds. Applications of decellularized grafts can replace the impaired ECM of diabetic wounds, providing ECM proteins such as collagen, glycosaminoglycans, proteoglycans and glycoproteins, allowing host cells to infiltrate, modulate the immune response and promote angiogenesis and the formation of granulation tissue [ 103 , 104 ]. There are several commercially available decellularized grafts for wound healing, Integra (Johnson & Johnson) [ 105 ], Oasis (Cook Biotech) [ 106 ], Alloderm (Allergan) [ 107 ], Primatrix (TEI Bioscience) [ 108 ]. Their manufacturing methods vary resulting in different mechanical properties of each product and the ability to support skin regeneration [ 109 , 110 ].

Several studies have investigated the use of decellularized grafts as a MSC delivery platform. One of these studies has shown that rat AD-MSCs seeded on a decellularized graft secreted various cytokines (e.g. HGF, VEGF, TGFβ, bFGF) that stimulated the migration and proliferation of fibroblasts, eventually resulting in improved wound closure (13 ± 0.37 days compared with 20 ± 0.71 days in scaffold alone group and 27 ± 0.44 days in no-treatment group) in a diabetic rat model [ 111 ]. In another study, mouse BM-MSCs were delivered by a graft that was decellularized from normal mouse skin. After transplanting this bio complex into a full-thickness cutaneous wound site in the diabetic mouse, the wound demonstrated an increased percentage of wound closure and significantly accelerated angiogenesis and reepithelialisation compared with no-treatment controls. The synthesis of collagen type I fibres was seen to be increased during diabetic wound healing, monitored using a novel multiphoton microscopy, indicating a potential mechanism of wound healing [ 98 ]. Decellularized dermal matrix incorporating reduced graphene oxide as a cell delivery platform has shown high stability and strong mechanical properties. This decellularized graft has been used to deliver mouse BM-MSCs to a diabetic mouse wound model resulting in a microenvironment for stem cell attachment, migration and proliferation, with robust vascularization and collagen deposition during wound healing [ 112 ]. Furthermore, human UC-MSCs delivered by a decellularized dermal matrix to the diabetic rat wound showed that the proliferation and differentiation of human UC-MSCs on the decellularized dermal matrix were regulated by activated Wnt signalling pathway, ultimately promoting the healing of the diabetic wound [ 113 ].

Clinical trials using scaffold-mediated delivery of MSCs for diabetic wound healing

Currently, 13 clinical trials using scaffold-based delivery of MSCs to treat diabetic patients with foot ulcers are registered with ClinicalTrials.gov (Table 3 ). 11 of these trials are using a hydrogel scaffold for MSC delivery, and 2 are using a sponge scaffold. In spite of the very large pre-clinical dataset available and the 13 registered clinical trials of scaffold mediated MSC delivery, only one clinical study has been published to our knowledge. In this phase 2 clinical trial (No. NTC02619877), an allogeneic AD-MSC hydrogel sheet has been developed and approved to be a commercial product by Food and Drug Administration of Korea (study code ALLO-ASC-DFU-201). 59 patients with diabetic foot ulcers were enrolled in this trial for a maximum of 12 weeks. Patients treated with this MSC-hydrogel sheet reached 82% of complete wound closure at week 12 compared to 53% of complete wound closure in patients without treatment. No adverse effects were observed after treatment, indicating hydrogel delivered AD-MSCs is efficient, effective and safe in the treatment of diabetic wounds [ 114 ]. An important feature of this MSC-hydrogel graft was the ability to cryopreserve and store while maintaining, stability for long periods of time [ 114 ]. In another case study, placenta derived MSCs (cell number: 1 × 10 6 cells/cm 2 ) encapsulated in a sodium alginate hydrogel was topically administrated to the foot ulcer of a patient with type 2 diabetes mellitus. The wound healed completely after 3 weeks of treatment, with improved foot pain, no toxicity and no relapse during the subsequent 6 months follow-up visit [ 115 ]. However, this is only a case study and further evaluation is needed. In addition, there is one clinical study reported which evaluated the effect of a collagen sponge scaffold delivering MSC-like dermal autologous micro-grafts (obtained from mechanical disaggregation of small pieces of skin tissue) to diabetic patients with foot ulcers. These dermal micro-grafts express MSCs markers (CD34, CD73, CD90 and CD105) in vitro and maintained their viability and proliferative property in the collagen scaffold. After applying this dermal micrograft-collagen scaffold bio-complex to the site of ulcers, the skin samples express increased level of insulin-like growth factor and TNF-β and decreased level of EGF, PDGF and their receptors compared with healthy skin samples. Treatment of these ulcers with this bio-complex resulted in improved wound closure and better quality of life for the patients [ 116 ].

Interestingly, 9 out of the 13 clinical trials used AD-MSCs as a cell source despite a large number of pre-clinical studies reporting therapeutic benefits with the use of the three major sources (bone marrow, adipose and umbilical cord) [ 65 , 95 , 111 ]. This could be related to the feasibility of clinical translation, where all of them show advantages and disadvantages. BM-MSCs showed great therapeutic potential in wound healing and are suitable for autologous transplantation [ 117 ]. However, their isolation requires an invasive procedure and low cell numbers, limiting their clinical translation [ 118 ]. In recent years, UC-MSCs have gained more attention in the field as an alternative source; they can be easily isolated using non-invasive procedures and yield a large number of cells from a young donor [ 119 ]. Moreover, they have shown interesting therapeutic abilities due to their low immunogenicity and immuno-regulatory properties [ 120 ]. Akin to BM-MSCs, AD-MSCs have been shown to be ideal for autologous application; adipose tissue can be obtained with less invasive procedures and yield a higher number of cells, easily meeting clinical needs [ 121 ]. However, both sources are isolated from adult tissues and donor health status or other intrinsic factors, such as the site of tissue collection in the case of AD-MSC, could result in underlying effects upon cellular characteristics that hinder their therapeutic potential [ 119 ]. Future studies should consider in-depth investigation of head-to-head biological and therapeutic differences among these sources and whether these differences have implications in the context of diabetic wound management.

Besides defining optimal cell source, there are many other bottlenecks hindering the translation of results obtained at the laboratory bench to the clinic and ultimately to the marketplace. These include the absence of a globally shared standard manufacturing process and the high level of regulatory diversifications across countries which create crucial challenges for international clinical trial collaborations and cross-country marketing procedures [ 122 ]. In addition, the mainstream widely accepted treatment of neuropathic diabetic foot ulcers is debridement and off weight bearing and clinical trials do not always include state of the art current clinical treatment in the control group. This also leads to poor uptake by medical practitioners of advanced therapies. Finally, re-imbursement issues and cost of goods impact on the utilization of these advanced therapy products in standard clinical practice. It would be useful if researchers interested in clinical application consider the translational requirements from the earliest stages of research so that experiments can be designed in a manner suitable for inclusion in a regulatory dossier when applying for approval to undertake a clinical trial. There is also a need for careful clinical trial design as outlined previously by experts in the field [ 123 , 124 ]. Partnerships with industry will also be crucial to enable translation.

Conclusions

MSCs are attractive therapeutic agents for use in diabetic wound healing, whilst biodegradable scaffolds provide a physiologically relevant three-dimensional environment for their optimal growth and localisation at wound bed. Pre-clinical studies have demonstrated that delivering MSCs via a variety of different scaffolds to diabetic wounds accelerates healing and enhances skin regeneration. In spite of this, there is limited clinical trial data available on the use of scaffold-based MSC delivery for treatment of diabetic wounds. Issues regarding safety, efficacy and cost of the MSC-scaffold graft in clinical applications should be considered from an early stage of research and properly addressed. Therefore, an interdisciplinary approach involving biomedical scientists, clinicians, biomaterial engineers, industry and regulators will be necessary to develop a scaffold-based cell therapy product suitable for clinical application.

Availability of data and materials

Not applicable.

Abbreviations

Adipose-derived mesenchymal stromal cells

Bone marrow-derived mesenchymal stromal cells

Basic fibroblast growth factor

Extracellular matrix

Epidermal growth factor

Extracellular vesicles

Hyaluronic acid

Hepatocyte growth factor

Hypoxia-inducible factor

Intercellular adhesion molecule-1

Interleukin

Insulin secreting cells

Metallopeptidase

Mesenchymal stromal cells

Platelet-derived growth factor

Poly(ethylene glycol)

Poly(ethylene glycol) diacrylate

Stromal cell-derived factor

Silk fibroin

Streptozotocin

Transforming growth factor-β

Tissue inhibitor matrix metalloproteinase 1

Tumour necrosis factor-α

Umbilical cord-derived mesenchymal stromal cells

Vascular endothelial growth factor

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Acknowledgements

This publication has emanated from research supported in part by a grant from Science Foundation Ireland (SFI) and the European Regional Development Fund (ERDF) under grant number 13/RC/2073_P2.

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Dimitrios I. Zeugolis

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Du, S., Zeugolis, D.I. & O’Brien, T. Scaffold-based delivery of mesenchymal stromal cells to diabetic wounds. Stem Cell Res Ther 13 , 426 (2022). https://doi.org/10.1186/s13287-022-03115-4

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Connecting lab-grown brain cells provides insight into how our own brains work

The idea of growing a functioning human brain-like tissues in a dish has always sounded pretty far-fetched, even to researchers in the field. Towards the future goal, a Japanese and French research team has developed a technique for connecting lab-grown brain-mimicking tissue in a way that resembles circuits in our brain.

It is challenging to study exact mechanisms of the brain development and functions. Animal studies are limited by differences between species in brain structure and function, and brain cells grown in the lab tend to lack the characteristic connections of cells in the human brain. What's more, researchers are increasingly realizing that these interregional connections, and the circuits that they create, are important for many of the brain functions that define us as humans.

Previous studies have tried to create brain circuits under laboratory conditions, which have been advancing the field. Researchers from The University of Tokyo have recently found a way to create more physiological connections between lab-grown "neural organoids," an experimental model tissue in which human stem cells are grown into three-dimensional developmental brain-mimicking structures. The team did this by linking the organoids via axonal bundles, which is similar to how regions are connected in the living human brain.

"In single-neural organoids grown under laboratory conditions, the cells start to display relatively simple electrical activity," says co-lead author of the study Tomoya Duenki. "when we connected two neural organoids with axonal bundles, we were able to see how these bidirectional connections contributed to generating and synchronizing activity patterns between the organoids, showing some similarity to connections between two regions within the brain."

The cerebral organoids that were connected with axonal bundles showed more complex activity than single organoids or those connected using previous techniques. In addition, when the research team stimulated the axonal bundles using a technique known as optogenetics, the organoid activity was altered accordingly and the organoids were affected by these changes for some time, in a process known as plasticity.

"These findings suggest that axonal bundle connections are important for developing complex networks," explains Yoshiho Ikeuchi, senior author of the study. "Notably, complex brain networks are responsible for many profound functions, such as language, attention, and emotion."

Given that alterations in brain networks have been associated with various neurological and psychiatric conditions, a better understanding of brain networks is important. The ability to study lab-grown human neural circuits will improve our knowledge of how these networks form and change over time in different situations, and may lead to improved treatments for these conditions.

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Human brain

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Materials provided by Institute of Industrial Science, The University of Tokyo . Note: Content may be edited for style and length.

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Tatsuya Osaki, Tomoya Duenki, Siu Yu A. Chow, Yasuhiro Ikegami, Romain Beaubois, Timothée Levi, Nao Nakagawa-Tamagawa, Yoji Hirano, Yoshiho Ikeuchi. Complex activity and short-term plasticity of human cerebral organoids reciprocally connected with axons . Nature Communications , 2024; 15 (1) DOI: 10.1038/s41467-024-46787-7

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Paralyzed man who can walk again shows potential benefit of stem cell therapy

A Mayo Clinic study used a patient's stem cells to help repair the spinal cord.

A man who was paralyzed from the neck down after a surfing accident seven years ago is now able to stand and walk on his own , thanks in part to a potentially groundbreaking stem cell treatment.

Chris Barr was the very first patient in a Mayo Clinic study that collected stem cells from his own stomach fat, expanded them in a laboratory to 100 million cells and then injected the cells into Barr's lumbar spine.

Over five years after undergoing the therapy, Barr said he is continuing to gain more independence and get faster at walking.

"I never dreamed I would have a recovery like this," Barr told ABC News' Will Reeve. "I can feed myself. I can walk around. I can do day-to-day independent activities."

Barr shared an update with Reeve on his own progress as Mayo Clinic published new data showing the success of the stem cell treatment in a clinical trial involving 10 patients, including Barr.

PHOTO: Chris Barr regained the ability to walk after undergoing stem cell treatment at the Mayo Clinic.

According to the trial's results, published Monday in the journal Nature Communications , seven of the 10 patients experienced increased strength in muscle motor groups and increased sensation to pinpricks and light touch.

MORE: Artificial intelligence used in medical procedure to help paralyzed man walk

Three patients in the study had no response to the stem cell therapy, meaning they did not get better or worse, according to the Mayo Clinic, based in Rochester, Minnesota.

"These findings give us hope for the future," Dr. Mohamad Bydon, a neurosurgeon and spinal cord researcher at the Mayo Clinic and the study's lead author, told Reeve, who is also the director of The Christopher Reeve Foundation, a nonprofit "dedicated to curing spinal cord injury," according to its website. The foundation, named in honor of Will Reeve's late father, was not involved in the funding of Bydon's research.

Bydon's research at the Mayo Clinic is a Phase 1 study that began in 2018.

The newly published results of the study show that of the seven patients who saw improvement after the stem cell therapy, each moved up at least one level on the American Spinal Injury Association -- or ASIA -- Impairment Scale, which has five levels documenting patients' function.

"This trial shows us that stem cells are safe and potentially beneficial in the treatment of spinal cord injury," Bydon said. "This can be a milestone in our field of neurosurgery, neuroscience and of treating patients with spinal cord injury."

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Bydon and other researchers are still trying to understand how and why the stem cells interact with the spinal cord to result in progress for some patients, and additional research is underway among a larger group of people to further assess risks and benefits.

In Barr's case, he told Reeve in 2019 he began to quickly see improvements, like getting feeling back in his legs, after undergoing the stem cell treatment.

PHOTO: Chris Barr speaks to ABC News’ Will Reeve about the progress he’s made in recovering from paralysis with the use of stem cells.

Now five years later, he described making further long-term improvements, like being able to walk for consistent intervals without assistance.

"I'm just thrilled that there are people taking bold steps to try and do research to cure this," Barr said. "It's been a wild ride and it's not over yet."

Dr. Priscilla Koirala, a member of the ABC News Medical Unit, contributed to this report.

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Stem Cell Research and Health Education

Stem cells are being touted as the greatest discovery for the potential treatment of a myriad of diseases in the new millennium, but there is still much research to be done before it will be known whether they can live up to this description. There is also an ethical debate over the production of one of the most valuable types of stem cell: the embryonic form. Consequently, there is public confusion over the benefits currently being derived from the use of stem cells and what can potentially be expected from their use in the future. The health educator’s role is to give an unbiased account of the current state of stem cell research. This paper provides the groundwork by discussing the types of cells currently identified, their potential use, and some of the political and ethical pitfalls resulting from such use.

INTRODUCTION

Stem cells are believed to be one of the greatest untapped resources currently available for the prevention and treatment of many diseases. Inasmuch as current knowledge of stem cells is a combination of scientific reality and cautious speculation, considerable research is required to identify the true, long-term potential for medical advances from these cells. As health resources professionals, communicators, and advocates, 1 health educators are in a position to advance the public dialogue about this promising technology. This article offers a general overview of stem cells, their potential for extending life and improving its overall quality, and some thoughts on the role of health educators with regard to professional and lay audiences.

WHAT ARE STEM CELLS?

Stem cells are template cells found throughout the body that can grow to become cells with specialized functions. 2 – 6 These cells replicate to generate “offspring” cells that can be either stem cells (and hence, self-renewing) or specialized cells (i.e., differentiated cells) that play a specific role—becoming blood, bone, brain, or skin cells, among others. 7 Stem cells, therefore, have the potential to act as repair systems for replacement of damaged cells. 2 – 6 The field in which a great deal of research is currently underway to determine the use of stems cells in the treatment of diseases and injuries is called “regenerative medicine.” Under “normal” conditions stem cells continue to replicate until they receive a signal to differentiate into a specific cell type. 8 When stem cells receive such a signal they first become progenitor cells, and later, the final mature cell type. Determination of the different signals that cause the stem cell to become a specific type rather than just continue to replicate is important (and, in some cases, it is the absence rather than the presence of a signal that is the important factor). 8 The ability of stem cells from one area to differentiate into another completely different type is known as plasticity, and embryonic stem cells appear to be the “most plastic” of the four types discussed below. 2 – 6

Stem cells are described as being of a specific cell line, dependent on the characteristics and location of the original template cells from which all future offspring cells have grown (reflecting the self-renewing capability of the cells). Assuming that no contamination of the cell line occurs as a result of mutations or infections, and no differentiating triggers occur, the cell lines could potentially grow ad infinitum. 2

DIFFERENT TYPES OF STEM CELLS

There are several types of stem cells: embryonic stem cells, fetal stem cells, adult stem cells, embryonic germ cells, and amniotic and umbilical cord stem cells. These stem cell varieties and their distinct properties are discussed below.

Embryonic and Fetal Stem Cells

The development of an organism can be compartmentalized into several stages. 9 Following the union of the egg and sperm, the initial four to five days from conception are characterized by a period of rapid cell division. A “ball” of 50 to 150 cells known as a blastocyst is created, so named because it is a hollow sphere. The blastocyst is composed of three parts: the trophoblast or outer surface, the blastocoel or inner cavity, and the inner cell mass found inside the blastocoel which is composed of stem cells. 9 These inner-lying cells are said to be “embryonic” even though the term embryo does not technically apply until after this initial two-week stage.

The next eight-week stage is characterized by cell growth and multiplication. Following this eight-week stage, the organism has recognizable structures and is classified as a fetus. At this time, embryonic stem cells continue to proliferate and are said to be pluripotent or plastic, meaning that they can differentiate into almost any type of cell that makes up the body. 10 The embryonic stem cell is believed by many scientists to be the most useful for potential medical treatments, but its use is restricted by federal legislation (described later in this article). Existing stem cells for medical research can come from four primary sources: existing stem cell lines, aborted or miscarried fetuses, discarded embryos from fertilization treatments, or cloned embryos. Only the first source can be used in federally funded research programs, however. 11 , 12

The cloning of embryos is another controversial area of research. The cloning of humans to full term is banned almost worldwide. 13 , 14 In some cases, short-term cloning has been performed to allow for the generation and extraction of stem cells, followed by the termination of the cloned embryo by the sixth day after fertilization. Cloning of some animals has been allowed to proceed to full term; the first and most famous example was the work of Scottish scientists resulting in the creation of a sheep known as “Dolly.” 15 That achievement became the driving force for new regulations to prevent a similar event occurring with human cells. The latest evidence suggests that cloned cells do not “reset their longevity clocks,” thus resulting in reduced lifespan. Furthermore, not only is the success rate of cloning low, but the cloned organism is beset with problems, some of which may not become apparent until adulthood, assuming life extends to that age. 16 , 17

For research to occur with embryonic stem cells, the inner cell mass of the blastocyst is extracted (thus destroying the embryo) and grown in cell culture. 18 , 19 This process enables cells to grow on plates coated with a feeder layer that provides anchorage and nutrients. The stem cells become attached to the plate and grow in the nutrient broth (i.e., cell culture media tailored to the specific needs of the cell line being grown). 18 , 19 As the cells proliferate they fill the plate until a point is reached where they would be forced to compete for space and nutrients. Shortly before such competition breaks out, the cultures are replated at the original cell density (meaning that one starting plate could be divided across two or more plates) and the process is repeated. This procedure is known as “passaging.” 20 After several months, the cells will number in the billions without differentiating or changing in any detectable way. They can either be frozen for storage or continue replicating. However, there is some evidence that with continued passaging, a point may be reached in which the cells become less stable with respect to their ability to replicate, differentiate, or avoid mutations. 21 This instability seems to be particularly true when adult and embryonic stem cells are compared (see below).

Fetal stem cells, typically obtained following abortion or miscarriage, are believed to be as pluripotent as their embryonic counterparts, though they occur at a later stage than the true embryonic stem cell. 22 Several biotechnological companies are experimenting with these cells as treatments for a myriad of diseases. For instance, ReNeuron, Inc. (UK) has several cell lines derived from the fetal brain that they are testing for the treatment of neurodegenerative disorders, including stroke, Parkinson’s disease, and Alzheimer’s disease. 23 , 24

Adult Stem Cells

A small number of stem cells can be found in adult humans at specific locations, such as in the bone marrow or the subventricular zone of the brain. 25 , 26 Until the discovery of these and other cells in the central nervous system, it was believed that the brain was the only organ that could not replicate. However, it is now clear that certain regions of the brain may have some limited capability to replace damaged or dead cells as a consequence of endogenous stem cells. 27 , 28

Whereas embryonic stem cells are derived from the inner cell mass of the blastocyst, knowledge of the origin of the adult stem cell is less certain. Its source could potentially be the same, with the adult stem cell being many generations removed from the original source. If this speculation is true, then one would expect the body to have large numbers of these cells, which it does not. It has therefore been suggested that halting of replication is the means by which the number of stem cells found in the organs of the body is limited. 29 The stem cells are said to have entered a state of quiescence, until they receive an activation signal due to cell damage. Determination of the signal that triggers adult stem cells to “wake up” is critical to maximizing their benefit. In addition, identification of what makes the cells quiescent is of considerable merit. One study revealed the presence of a “master switch” that can trigger the change from embryonic to adult stem cell characteristics, suggesting that this signal may originate from the same source. 30

There is considerable debate as to how pluripotent adult stem cells are. The original belief was that they were not as versatile, healthy, or durable as embryonic stem cells because they appeared to be limited to forming only cells of a similar origin (e.g., bone marrow stem cells could only produce blood cells). Consequently, these cells became known as multipotent cells. These characteristics meant that adult stem cells would be harder to manipulate or control compared with embryonic cells. Also, due to their presence in adults, it is likely that the cells could have accumulated abnormalities through continuous exposure of the organism to environmental hazards (such as viruses) or to replication errors. 31 , 32 The latter problems are normally corrected, but with the aging organism, the ability to correct replication errors is believed to diminish. 32 , 33 In the majority of cases, the ability of adult stem cells to replicate also appears to be limited compared with embryonic stem cells, thus reducing their usefulness. 34 However, these cells do have an advantage over embryonic stem cells: theoretically, they can be removed from a patient, grown in culture, and then returned to the patient. 35 Therefore, they would not induce an immunological rejection response that may be seen with embryonic stem cells. 35 , 36 In addition, there is more flexibility in using these cells than human embryonic stem cells, especially with regard to federal funding.

Some research shows that certain adult stem cells can differentiate into a number of varied cell types, including neurons 37 – 39 of the peripheral and central nervous system. However, this observation may not be true of all adult stem cells, and more research is required to determine how useful these cells might be for use in treating human disease and injury.

Most research on adult stem cells is based on mesenchymal cells, i.e., cells from regions originally derived from the mesodermal layer of the embryo. These cells include connective tissue and, in particular, bone marrow and muscles. They are multipotent cells and are a relatively homogeneous population of mononuclear progenitor cells that can be made to differentiate into specific cell lines following environmental cues. Additionally, there are stromal stem cells found in the bone marrow, which are a more heterogeneous population of different cell types with varying degrees of proliferation and differentiation potential. 40 Adult stem cells also can be found in children, in the placenta, and in blood from the umbilical cord. These specialized cells are discussed below.

Embryonic Germ Cells

Germ cells are the precursors to the gametes (egg and sperm) and are therefore found in adult testes and ovaries, and in the areas of the embryo that ultimately differentiate into testes or ovaries. 41 These cells appear to be as pluripotent as other embryonic stem cells. However, they have been found to differentiate spontaneously, which would suggest that there is less control over their development than with other stem cells. 42

Two studies 43 , 44 suggest that adult stem cells can be easily derived from germ cells of both sexes. Further research is needed to explore the validity of this hypothesis, though the findings are certainly intriguing and potentially useful.

Amniotic Fluid (or Placental) and Umbilical Cord Blood Stem Cells

The amniotic fluid that surrounds and protects a developing fetus in its mother’s uterus, as well as the placenta, have also been shown to contain stem cells. 45 An amniocentesis procedure—where amniotic fluid is collected through the insertion of a long, thin needle into a pregnant woman’s abdomen to check for abnormalities, including Down syndrome—is generally considered safe for both the mother and embryo. 46 The collected amniotic fluid is normally discarded once testing is complete, but now that it has been found to contain stem cells, there is potential for further research and storage of such fluid. The current belief is that amniotic fluid contains a mixture of embryonic and adult stem cells. 47 , 48 Testing of these cells has been limited to date. It is believed that they are able to differentiate into a variety of cell types, but it is not known whether they are as pluripotent as other types of stem cells. Some authorities have suggested they could be used as a potential treatment for diabetes. 49

Umbilical cord blood contains low levels of stem cells as well as a number of hematopoietic (blood forming) cells, including lymphocytes and monocytes. There is a considerable amount of research focusing on umbilical cord blood for the treatment of stroke, myocardial infarction, and a variety of blood-related disorders, with some degree of success. 50 – 53 The benefits of such blood have already been demonstrated in the treatment of hematopoietic disorders, with over 6,000 transplants being performed worldwide since it was first used to treat a five-year-old child afflicted with Fanconi anemia in 1988. 50 And there is good experimental evidence that it can help with other disorders as well. 53 , 54 However, it is unclear precisely how these benefits are obtained. Current evidence suggests that in many cases it is not the stem cells per se that provide the benefit, but rather the growth factors these cells release. Some research shows that umbilical cord blood cells do seem to have the ability to become neuronal-like cells in vitro, but do not appear to produce neurons of any significant number in animal models of stroke. 53 , 54

The current research interest in umbilical cord blood cells 53 , 54 has resulted in the formation of many companies worldwide that allow public and private storage of these cells. As a result, at least 18 states have proposed legislation to encourage and inform the public about this potential resource, and in several cases to provide funding for the setting up and/or running of umbilical cord cell banks (see http://www.ncsl.org/programs/health/genetics/geneticsDB.cfm for a searchable database of such legislation). Additionally, official Japanese, European, and Australian banks exist, as well as the many private companies that are currently “getting in on the act.” 55 – 57 This resource could prove to be valuable. Although the potential benefit of these cells still remains relatively unexplored, the practice of banking them already has at least one undeniable benefit: providing donors with a source of their own cells, which considerably reduces the chance of rejection if they ever do need them for medical reasons.

Two other recent papers have demonstrated an additional potential source of adult multipotent stem cells: menstrual blood. 58 , 59

POTENTIAL USES OF STEM CELLS

Adult stem cells derived from bone marrow (i.e., the hematopoietic system) have been used frequently over the past 30 years for successful treatment of numerous blood-based disorders. Current treatments include nuclear radiation exposure and transplantation for the treatment of genetic diseases or cell cancers of the blood and the blood-forming system. 40 , 60 – 63

According to a White House report, there are currently more than 1,200 non-embryonic stem cell clinical trials under way, while none are being performed using embryonic cells. 64 The freeze on federal funding to support embryonic studies, rather than a lack of efficacy, is most likely a major factor behind this statistic. It is important to remember, however, that embryonic stem cell research has never been illegal in the United States; it just cannot be funded from federal sources other than those lines that were approved in August 2001. It is also noteworthy that adult stem cells have been researched for three decades, whereas embryonic stem cell research is considerably more recent, with the first human embryonic stem cell being isolated in 1998 at the University of Wisconsin–Madison by James Thomson. 18 That discovery led to several patents/licenses by the Wisconsin Alumni Research Foundation (WARF), further restricting the use and research of such cells, given the expense of purchasing them. These patents were revoked in April 2007 by the U.S. Patent and Trademark Office, 65 but WARF appealed the decision. In March 2008, WARF’s appeal was upheld. 66 To provide cells to researchers, the National Institutes of Health has established a subsidy that allows the purchase of cell lines approved in August 2001, at much reduced rates, thus resolving some of the previous issues related to their use.

Many of the adult stem cell trials are also oncology studies rather than regenerative medicine studies. 67 , 68 Ongoing clinical studies include phase II trials in which patients suffering from myocardial ischemia have their own adult bone marrow stem cells transplanted into their heart, theoretically increasing revascularization of the affected areas. 69 , 70 Additional cardiac therapies are summarized in a review by Ramos and Hare. 71

A myriad of basic research is underway worldwide on both embryonic and non-embryonic stem cells derived from a number of sources. This research encompasses treatment of various disorders including organ regeneration, cardiovascular improvements, diabetes, and neurodegenerative conditions. They comprise the complete continuum of research from preliminary explorative studies through preclinical and clinical trails. Promising results include the promotion of liver regeneration by bone marrow stem cells in patients with hepatic malignancies, 72 the formation of blood vessels in mice from human embryonic stem cells that have been made to differentiate into endothelial precursor cells, 73 the treatment of stroke and heart ischemia animal models by human umbilical cord blood transplants in rats, 51 , 53 , 54 and the ability of embryonic stem cells to differentiate into functioning heart tissue (myocytes). 74 Adult stem cells also have been used for the latter purpose, but the differentiated cells appear to impair heart function. However, preliminary data from a clinical phase I trial of an intravenous formulation (Provacel) of adult bone marrow–derived mesenchymal stem cells appears to demonstrate some benefit in decreasing subsequent problems among heart attack patients (Schaer, American College of Cardiology’s Innovation in Intervention, March 25, 2007). Also, Yacoub 75 announced that his team has been able to grow a heart valve from bone marrow stem cells using a collagen scaffold. This procedure has yet to be tested to determine if the valve is functional in vivo , but it clearly represents a promising discovery. Similarly, preliminary testing of the recently discovered stem cells in amniotic fluid for treating heart disease has demonstrated some encouraging results that require further study and verification. 76 Unfortunately, transplantation of these cells has been accompanied by a strong immunological response.

Elsewhere, a study using embryonic stem cells has shown considerable improvement in mice specially bred to exhibit symptoms of Sandhoff disease, a childhood disorder. 77 The implanted cells appear to function by replacing the neurons killed by the disease, as well as restoring normal levels of the enzyme hexosaminidase (low levels cause the disease). The disease was found to eventually return, but Lee et al. 78 believe that additional treatments could inhibit recurrence and are conducting further research in this area.

Preliminary findings from other studies involving fetal neural stem cells in culture and in animals have shown rescue of retinal cells after injury or disease. 79 This observation appears to demonstrate a restorative rather than a replacement action by these cells.

In general, considerable research is underway to ensure that the development of treatments involves only those cell types being sought, and that it includes ways of ensuring desired outcomes—i.e., controlling the stem cells so that they form the desired cells and do not proliferate indefinitely, which could lead to malignancy once transplanted. Achieving such outcomes may constitute one of the biggest stumbling blocks to stem cell research. One possible method would be to differentiate the cells before transplantation; Keller 79 has summarized various attempts at this method. Yet, a study involving transplantation of stem cells obtained from the human central nervous system into a primate Parkinsonian model resulted in behavioral improvements and integration of cells without tumor formation. 80 Therefore, predifferentiation of cells before transplant may not be necessary, though further research is required to be sure that this is the case. This avenue of research is likely to see many initiatives, given the anticipated dividends.

Additionally, study of the body’s ability to reject “foreign” tissue is also important because certain embryonic tissue is likely to have the ability to induce a significant immunologic response. Some studies are now suggesting that immature embryonic stem cells and umbilical cord blood cells are not as likely to cause an immunological reaction as differentiated adult stem cells. 81 – 83 With adult stem cells, harvesting from the same patient undergoing the transplant generally eliminates this problem.

A few studies have found that co-transplantation of two or more different types of cells has resulted in a synergistic effect that maintained their survival and execution of beneficial effects. For instance, the co-culture of amniotic epithelial and neural stem cells promoted neuronal differentiation of the latter. 84 Both trophic support and direct contact between the two cell types appeared to have important but independent effects on the neuronal survival and differentiation.

One caveat to consider in stem cell treatment of disease is that the replacement of dying cells by new ones is only a temporary solution because whatever resulted in the death of the cells initially—unless purely intrinsic to the dying cells themselves or only a onetime event—will eventually prove lethal to the new cells, too. This phenomenon has been demonstrated in a paper on fetal tissue grafts for the treatment of Parkinson’s disease. 85 Consequently, calling stem cells a “cure” for diseases is really a misnomer; instead, calling them the “best available treatment” may be more accurate at present. This caveat makes the assumption that stem cell transplants are replacing the dying cells. Studies on stroke models using umbilical cord blood–derived stem cells do not support the idea of replacement, but do show an improvement in the size of the stroke lesion and behavioral markers. 53 , 54 Some of their benefit may be more related to controlling the inflammatory response that causes cell death or to promoting more rapid healing. A study by Capone et al. 86 demonstrated that stem cells do act in this fashion, modifying the microenvironment following stroke to afford neuroprotection, rather than replacing “sick” cells. Similar findings have been observed in other studies, including the eye experiments mentioned previously. Thus, stem cells may help to support the cells that are already present and protect them from further injury or death due to the factors that cause or perpetuate the initial disease or injury. This support in turn leads to another consideration: are pluripotent cells necessarily better than multipotent ones? Assuming that adult stem cells from a specific source (e.g., adult stem cells from the brain) can differentiate into the required replacement cell (e.g., neural cells) or provide the required supporting factors, they do not need to be pluripotent. Therefore, pluripotent (embryonic stem) cells would only be required when adult stem cells are not present or cannot differentiate into the cell of interest or produce the necessary factors to give the desired result. Consequently, research on both pluripotent and multipotent cells would seem to still be necessary. 87

Not only does stem cell research provide direct cell replacement benefits or improve the survivability of “sick” or “injured” cells, it also offers considerable insight on what causes cells to proliferate and differentiate—an important phenomenon to understand in the fight against cancers and in general research dedicated to the development and normal life cycle of cells. 88 – 92 Studies of stem cells could, therefore, have far-reaching implications that are not limited to just disease treatment. 88 – 94 Finally, stem cells could also be used to model organs for the testing of drugs or new surgical techniques—another potentially powerful benefit of stem cell research. 95 , 96

PREDOMINANT CONTROVERSIES ABOUT STEM CELL RESEARCH

There are four main controversies currently surrounding stem cells. Perhaps the most significant involves moral arguments regarding the use of embryonic material to harvest stem cells. The focus of this controversy is on when life begins—which some consider to be at conception—and whether any individual has the right to terminate a life. Strong spiritual and religious beliefs are frequently central to this controversy, and the practice is considered unacceptable by many. One study 97 suggested the possibility of removing one or a few stem cells without harming an in vitro–fertilized embryo prior to implantation, thus maintaining its viability. As of yet, however, it is unclear exactly what impact this action has on the growing organism and whether such studies can be confirmed. Consequently, because of the controversy over when life begins, many countries either ban embryonic stem cell research or severely restrict it. As indicated previously, only those embryonic stem cell lines approved for study in August 2001 can receive federal funding and support in the United States.

Three connected groups of scientists reported success in transforming normal mouse skin cells into embryonic stem cell–like cells via genetic manipulation. 98 – 100 Further research is required to confirm these findings and those of other studies 101 , 102 have translated this technique to human cells. Additionally, the transformed cells are prone to tumorigenesis, and therefore, would not be useful for transplantation in humans in their current form. This technique would not necessarily replace the use of embryo-derived stem cells, as further characterization is necessary to confirm that the cells do possess all of the same characteristics—including the same receptors and response to treatments. Nevertheless, it is a small step in the right direction for those opposed to embryonic sources.

A second controversy surrounding stem cell research is the apparent groundbreaking outcome of studies performed by a research team in South Korea. In 2004, this team reported in Science that they had obtained human embryonic stem cells from the nuclear transfer of oocytes (i.e., the replacement of the nucleus of an egg with that of an already differentiated cell). The following year, this team again reported in Science that they were able to generate patient-specific immune-matched embryonic stem cells for the treatment of diseases. In the end, the data were found to be fraudulent, and some of the female researchers had apparently been coerced to donate their own eggs for the process of obtaining stem cells, a significant ethical breach in the field. 103 As a result of these findings, both papers were retracted in 2005, and significant penalties were imposed on the researchers. This scandal cast a large shadow over the competitiveness in the field and the possible unethical means of obtaining stem cells for research purposes.

A third controversy has to do with stem cells’ alleged potential to produce malignancies once implanted due to their theoretically immortal nature (viewed as such because stem cells can reproduce ad infinitum ). Some research suggests that certain kinds of stem cells could cause cancer because a small number of defective stem cells have been found in tumors, where they may have acted as a seed. 104 Given their ability to proliferate continuously, these cells carry an increased likelihood of mutations, which in turn increases the probability that they will grow out of control and become cancerous. Therefore, their use in treatments could be fraught with problems, at least until a clearer understanding emerges regarding the signals that turn them on and off in their growth cycles. Adult stem cells are normally quiescent, meaning that identification of the process by which mutations occur could prove to be vitally important in preventing transplant tumorigenicity or in preventing cancers altogether.

Interestingly, studies using embryonic carcinoma cells—which are malignant, similar to stem cells, and generally derived from germinal cells—have provided some neurodegenerative improvement in animal models. 105 These cells can be made to differentiate into human neurons under retinoic acid treatment. When this conversion occurs, the cells appear to lose their malignant properties. 105 Once the mechanism for this process has been determined, it could be tested in stem cells, perhaps creating the ability to turn off the malignant characteristics of these cells.

At the same time, another recent study suggested that although stem cells—specifically, those obtained from bone marrow—may look like malignant cells, they do not necessarily function like them. In other words, stem cells may not be cancerous and may not be able to seed tumors. 106 Further research is required to determine whether this is true for all stem cells found in tumors, and whether they are acting as “developmental mimics” or seed tumors.

The fourth main controversy concerns whether adult stem cells are as beneficial as embryonic stem cells. A seminal paper from a group led by Catherine Verfaillie (see Jiang et al. 107 ) reported that adult stem cells from the bone marrow of rats, which they called “multipotent adult progenitor cells” (MAPCs), had the potential to differentiate into almost every type of cell in the body, a claim that previously applied only to embryonic stem cells. Unfortunately, little success has been made in replicating these results. More recent evidence suggests that the paper was flawed, adding further consternation to this area of investigation. 108 , 109 Subsequent research from a number of teams reported that when MAPCs could be successfully isolated from bone marrow using a different technique than that originally proposed, they did have the ability to become any type of blood cell but not other cells. But overall, it is still unclear whether this and other types of adult stem cells are as efficacious as originally proposed. 110 – 112 Criteria that stem cells have to meet to be classified as pluripotent have been proposed, 113 , 114 and few studies have actually met these criteria, with the majority being explained by cell fusion 115 and incorrect interpretation. 111 , 116 Thus, many researchers still believe that embryonic stem cells may provide more benefit due to their hypothetical ability to differentiate into all cell types, though most would prefer both avenues to be explored, acknowledging that adult stem cells could be useful in some circumstances.

Two independent studies by the groups of Yamanaka 101 and Thomson 102 may make this controversy a moot point. Expanding on the mouse studies 98 – 100 mentioned in an earlier section, they reported two similar methods of converting adult human skin cells into embryonic-like stem cells. This was achieved by the insertion of 4 genes that led to the reprogramming of the cells (interestingly, two of the genes differed between the research groups but had similar functions). This research has great potential but requires considerable additional testing to ensure that the embryonic-like stem cells behave in a similar fashion to embryonic stem cells obtained in the “normal” fashion. Additionally, there is the concern that one of the genes the researchers inserted was a cancer gene, which could increase the likelihood for tumorigen-esis using this approach. There is also concern over the retroviruses used to insert the genes, which can have potentially carcinogenic and other detrimental effects due to their ability to randomly insert the gene of interest into the genome. A major bonus of this approach is the ability to take the cells from the patients themselves and therefore reduce the likelihood of transplant rejection. There is also the potential to model a disease more directly by removing the affected cells from a patient and growing them in culture so that they can be characterized and compared with healthy cells. Research by Jaenisch’s group 117 has demonstrated that reprogrammed skin cells can treat the sickle cell anemia mouse model, thus confirming the potentially beneficial effects of such cells.

STATUS OF LEGISLATION ON STEM CELL USE

In the United States, federal funding for embryonic stem cell research from sources such as the National Institutes of Health is restricted by congressional legislation, which mandates that only cell lines approved in August 2001 be used in funded research. At that time, there were more than 60 lines, but only 20 have proven to be viable and available for general use. All of these cell lines have been grown on a mouse fibroblast feeder layer to restrict differentiation and only allow replication. Unfortunately, it has been found that these stem cells are likely contaminated with mouse proteins and sugars that could generate severe immunological responses following transplantation into humans to treat diseases. 118 However, some studies suggest that the proteins and sugars can be removed or cultured out to make the cells safer for human transplantation. 119 Newer procedures that use completely human components have been developed, so any future cell lines are unlikely to have this problem. Research involving adult stem cells is not limited under the current federal restrictions.

The 20 embryonic cell lines that are federally permissible represent only a small fraction of the genetically and immunologically heterogenous population of the world. 120 , 121 This limitation casts doubt over whether any treatments derived from these cell lines will be suitable for treating all of the ethnically diverse populations that exist in the United States and abroad. This limitation is both an incentive for developing additional cell lines and an important factor that should be considered with respect to all types of stem cells. The genetic diversity inherent in the world’s different ethnic groups implies that different ethnicities may respond in different ways to these cell lines. Therefore, any success found with these cells would need to be replicated using cell lines derived from other ethnic groups to determine their general use among the world’s population. 122

In 2006, a congressional bill was proposed to allow research on stem cells derived from embryos discarded after in vitro fertilization treatments. This bill was vetoed by the president based on ethical, moral, and religious concerns. The bill resurfaced following the 2006 midterm elections in which Democrats regained control of the House and Senate, but no change to the veto is likely under the current administration. 123

The restriction on federal funding for embryonic stem cell research led New Jersey to appropriate state funding for research on both embryonic and adult stem cells in early 2004. Ohio had previously proposed funding dedicated to adult stem cell research. The most well known example of funding at the state level is California, which proposed its own legislation in 2004 (Proposition 71) involving the sale of $3 billion in bonds to provide $295 million annually for 10 years to the funding of stem cell research. 124

Since then, several other states have sought endorsement of similar propositions ( Table 1 and Table 2 ). Currently, at least 33 states have specific guidelines with respect to the use of embryos in research, which in several cases (e.g., Arizona, South Dakota, Texas) conform to federal legislation. However, there is considerable variation among these states regarding their support of separate initiatives for stem cell research.

States That Are Encouraging Stem Cell Research

Sources: Compiled from various online reports, including www.ncsl.org/programs/health/genetics/embfet.htm , http://isscr.org/public/regions , and “Yahoo! Alerts Health News: Stem Cells” (all last accessed December 7, 2007).

States with Legislation Relating to Embryonic Stem Cell Use

The International Society for Stem Cell Research recently proposed international guidelines for the use of embryonic tissue to ensure uniform research and experimental practice worldwide. 125 At the core of these guidelines is that embryonic research should be rigorously overseen by sponsoring organizations or regulatory bodies with specific policies and procedures that conform to the recommendations of the scientific community. In all policies, no cloning is to be undertaken to create humans. The society’s policies also recommend the establishment of an institutional oversight committee to review and determine approval of all stem cell research. The use of “chimeras” (i.e., animals created with human cells) is allowed with approval from this committee. Further, the use of any cells donated for research purposes should require consent from those donating them. Regulations pertaining to stem cell use by state and country are kept reasonably up to date at the following websites:

http://www.ncsl.org/programs/health/genetics/embfet.htm
http://isscr.org/public/regions

Initially, the federal funding restriction was seen as detrimental to stem cell research. However, some scientists are now suggesting that the restriction has actually opened other funding opportunities that may be more helpful to the research community. As Table 1 shows, federal restrictions have created unprecedented state funding far exceeding any that the National Institutes of Health would likely provide. This alternative funding source has also piqued the interest of pharmaceutical companies. Such companies may be able to position themselves for a larger share of patents and licenses from state-funded research—they already have a near monopoly on drug therapies derived from this research. This apparent paradox was discussed in an opinion piece in The Scientist by Dr. Paul Sanberg. 126

STEM CELL RESEARCH AND HEALTH EDUCATION PRACTICE

Health educators are charged with numerous roles and responsibilities in the public sector. 1 These essential tasks intersect with current and anticipated research involving stem cells. What follows is an iteration of ways in which health educators might be expected to address relevant stem cell knowledge and research issues. Although not exhaustive, the points below highlight the importance of keeping public dialogue about this topic both vibrant and accurate.

Assessing Individual and Community Needs

Health education competencies and subcompetencies in this area include, but are not limited to, selecting valid sources of information about health needs and interests. The debate over stem cell research inevitably becomes enmeshed in moral arguments and political posturing, so it is important that scientifically accurate information and data be made prominent in the public eye. Health educators are positioned to translate technical information and make it accessible to the lay public and other interested consumers. Presently, although there are many avenues of availability for this information in the scientific and medical communities, it is far less available to the general public. What is needed are accurate sources of relevant stem cell data and other information that neither refute scientific discovery nor escalate optimism inappropriately or prematurely.

Planning, Implementing, and Administering Strategies and Programs

The highly diverse nature of the health information consumer includes different levels of health literacy, disparate ethical and moral belief systems, and widely varying learning styles. Health educators are professionally prepared as a group to respond to the needs of these different audiences by identifying individuals and groups who can best benefit from knowledge about stem cell research, incorporating appropriate organizational frameworks, establishing specific learning objectives based on assessment of baseline knowledge, assigning audience-specific modes of education delivery, and developing a program delivery method that includes optimal use of learning technologies.

Health educators are able to assess both knowledge and attitude shifts through the use of well chosen surveys and other assessment instruments. Moreover, health educators can infer needed future activities and programs that build either in a linear or a spiraling fashion on past activities. Stem cell research is a pioneering endeavor, and the knowledge shifts can, therefore, be rapid; the need for recurring data and information sources suitable for general and specific audience consumption is as dynamic as the shifting sands. Health educators are prime candidates for interpreting these changes, putting them in context, and making the necessary and relevant adjustments to the public’s informational needs.

Serving as an Education Resource Person

Health educators should be masters at retrieval of information that can be translated from technical to more audience-friendly language. As with their other resource functions, health educators should be able to match information needs with the appropriate retrieval systems; to select data and data systems commensurate with program needs; and to determine the relevance of various computerized health information resources, access those resources, and employ electronic technology for retrieving references. To enhance the match between information and audience, health educators should be positioned to perform readability assessments using such tools as the SMOG Test, 127 the Flesch Reading Ease Formula, 128 and other indices, 129 thereby increasing the likelihood that relevant information about stem cells will be understood.

Advocating for Education about Stem Cell Research

Health educators are expected to analyze and respond to current and future needs in health education. Particularly pertinent to stem cell research is the analysis of factors (e.g., social, demographic, political) that influence individuals who make decisions about the direction of, and restrictions on, stem cell research. Currently, the wise course may be for health educators to be as politically neutral as possible in organizing and communicating information about stem cell research—standing neither for nor against liberalization of current research postures by the federal government and other entities. Health educators, like any other professional group, are subject to their own biases, including those emanating from personal moral philosophy, ethical principles, or other convictions. Nevertheless, they are obligated to report on stem cell matters factually. They can also serve as advocates for promoting discussions in the public sector, at professional conferences, and in their own scientific literature. Finally, practice standards support health educators’ participation in continuing education on stem cell issues and their development of plans for ongoing professional development.

Stem cell research is a major area in biomedical research, one that could have a far-reaching impact on the overall health of the human race. Many people, professional and lay alike, obtain their knowledge from sources that present personal agendas or dubious interpretations of facts. In this article, we have endeavored to give a fair, balanced, and unbiased view—as much as our personal limits as scientists and individuals permit—of the potential of stem cells. We have also argued that health educators can position themselves to bring some orderliness to the debate about the merits of stem cell research and support a healthy dialogue among lay audiences as well as their own professional peers.

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COMMENTS

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Stem cells: highlights from research. Self-organizing models of the early heart, why dead cells can be therapeutic, and other studies. By. Anthony King. Follicle structures, including oocytes ...
Scaffold-based delivery of mesenchymal stromal cells to diabetic wounds
This paper discusses biomaterial-based MSCs therapies in diabetic wound healing and highlights the low conversion rate to clinical trials and commercially available therapeutic products. ... Bortz G, Vasen F, Sleeboom-Faulkner M. Global regulatory developments for clinical stem cell research: diversification and challenges to collaborations ...
Connecting lab-grown brain cells provides insight into how our own
Aug. 29, 2019 — Scientists have created miniature brains from stem cells that developed functional neural networks. Despite being a million times smaller than human brains, these lab-grown ...
Paralyzed man who can walk again shows potential benefit of stem cell
Bydon's research at the Mayo Clinic is a Phase 1 study that began in 2018. ... Bydon and other researchers are still trying to understand how and why the stem cells interact with the spinal cord ...
Stem Cell Research and Health Education
The fourth main controversy concerns whether adult stem cells are as beneficial as embryonic stem cells. A seminal paper from a group led by Catherine Verfaillie (see Jiang et al. 107) reported that adult stem cells from the bone marrow of rats, which they called "multipotent adult progenitor cells" (MAPCs), had the potential to ...

Stem cells: past, present, and future

Publication types

Recent advances in stem cell therapeutics and tissue engineering strategies

Types of stem cells for tissue regeneration

Development of stem cell-activating growth factors and peptides

Stem cells engineered with nanomaterials

Biomaterials enhancing the therapeutic efficacy of stem cells

3D bioprinting for tissue engineering

Application of 3D bioprinting technology for tissue regeneration

Conclusions

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Biomaterials Research

The impact of induced pluripotent stem cells in animal conservation

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Stem cells on regenerative and reproductive science in domestic animals

Somatic Cells, Stem Cells, and Induced Pluripotent Stem Cells: How Do They Now Contribute to Conservation?

The use of induced pluripotent stem cells in domestic animals: a narrative review

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Study documents safety, improvements from stem cell therapy after spinal cord injury

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Stem cells' mechanism of action not fully understood

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Revolutionizing Medicine: the Potential of Stem Cell Therapy

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Stem cells: highlights from research

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