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Advances in hair growth

Affiliations.

1 National and International Skin Registry Solutions (NISR), Charles Institute of Dermatology, University College Dublin, Dublin, Ireland.
2 Hair Restoration Blackrock; Dublin, Ireland.
3 Charles Institute of Dermatology, School of Medicine, University College Dublin, Dublin, Ireland.
4 St Helens & Knowsley NHS Trust, Prescot, UK.
5 Manchester University, Faculty of Biology, Medicine and Health, Oxford Road, Manchester, UK.
6 St. James's Hospital, Dublin, Ireland.
7 Netcare Greenacres Hospital, Port Elizabeth, South Africa.
8 Sinclair Dermatology, Melbourne, Australia.
PMID: 35156098
PMCID: PMC8808739
DOI: 10.12703/r/11-1

Hair is a deeply rooted component of identity and culture. Recent articles in this series have focused on scientific evidence relating to hair growth and new insights into the pathogenesis and mechanism of hair loss. This article reviews emerging evidence that has advanced our understanding of hair growth in both of these areas to provide a context for outlining current and emerging therapies. These include finasteride, minoxidil, topical prostaglandins, natural supplements, microneedling, low-level laser light, platelet-rich plasma, fractional lasers, cellular therapy, Wnt activators and SFRP1 antagonism.

Keywords: Alopecia; androgenetic alopecia; antiandrogens; exosomes; female pattern hair loss; fractional lasers; hair cycling; hair growth; low-level laser light; male pattern hair loss; micro-needling; minoxidil; platelet rich plasma; prostaglandins.

PubMed Disclaimer

Conflict of interest statement

DW has received personal fees (honoraria) from Janssen and Eli Lilly and Company (consultancy fees) and non-financial support (travel fees/grant) from Pfizer but not in relation to this article. RS is a principal investigator in clinical trials sponsored by Janssen, Eli Lilly and Company, Pfizer, Leo Pharma, Amgen, Novartis, Merck and Co., Celgene, Coherus BioSciences, Janssen, Regeneron, Medimmune, GlaxoSmithKline, Samson Clinical, Boehringer Ingelheim, Oncobiologics, Roche, Ascend, Dermira, AstraZeneca, Akesobio, Rhinestone, UCB, Aerotech, Sanofi, Connect, Arcutis, Arena, Sun Pharma, Bristol Myers Squibb, Abbvie and Galderma, outside the submitted work. NM, NF, and KY declare that they have no competing interests.Competing Interest: JR is consultant to Crown Aesthetics and the director of the Rapaport Hair Institute.No competing interests were disclosed.

Figure 1.. Miniaturisation of the hair follicle.

In a previous F1000 article, a model of…

Figure 2.. Androgenetic alopecia miniaturised follicles.

In androgenetic alopecia, there is a reduction in the…

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UC Irvine-led researchers reveal new molecular mechanism for stimulating hair growth

Findings may offer road map for next generation of therapies for androgenetic alopecia

Irvine, Calif., June 21, 2023 — The process by which aged, or senescent, pigment-making cells in the skin cause significant growth of hair inside skin moles, called nevi, has been identified by a research team led by the University of California, Irvine. The discovery may offer a road map for an entirely new generation of molecular therapies for androgenetic alopecia, a common form of hair loss in both women and men.

The study, published today in the journal Nature , describes the essential role that the osteopontin and CD44 molecules play in activating hair growth inside hairy skin nevi. These skin nevi accumulate particularly large numbers of senescent pigment cells and yet display very robust hair growth.

“We found that senescent pigment cells produce large quantities of a specific signaling molecule called osteopontin, which causes normally dormant and diminutive hair follicles to activate their stem cells for robust growth of long and thick hairs,” said lead corresponding author Maksim Plikus, UCI professor of developmental and cell biology. “Senescent cells are typically viewed as detrimental to regeneration and are thought to drive the aging process as they accumulate in tissues throughout the body, but our research clearly shows that cellular senescence has a positive side to it.”

The growth of hair follicles is well regulated by stem cell activation; these cells divide, enabling follicles to produce new hair in a cyclical manner. After each bout of hair growth, there’s a period of dormancy, during which the follicle’s stem cells remain inactive until the next cycle begins.

The study involved mouse models with pigmented skin spots that had hyperactivated hair stem cells and displayed accelerated hair growth, strongly resembling the clinical observations documented in human hairy skin nevi. Further detailed analysis of senescent pigment cells and the nearby hair stem cells revealed that the former produced high levels of a signaling molecule called osteopontin, for which hair stem cells had a matching receptor molecule called CD44. Upon molecular interaction between osteopontin and CD44, hair stem cells became activated, resulting in robust hair growth.

To confirm the leading role of osteopontin and CD44 in the process, mouse models lacking either one of these genes were studied; they exhibited significantly slower hair growth. The effect of osteopontin on hair growth has also been confirmed via hairy skin nevi samples collected from humans.

“Our findings provide qualitatively new insights into the relationship between senescent cells and tissue’s own stem cells and reveal positive effects of senescent cells on hair follicle stem cells,” said first and co-corresponding author Xiaojie Wang, UCI associate specialist in developmental and cell biology. “As we learn more, that information can potentially be harnessed to develop new therapies that target properties of senescent cells and treat a wide range of regenerative disorders, including common hair loss.”

The team included healthcare professionals and academics from the U.S., China, France, Germany, Korea, Japan and Taiwan.

“In addition to osteopontin and CD44, we’re looking deeper into other molecules present in hairy skin nevi and their ability to induce hair growth. It’s likely that our continued research will identify additional potent activators,” Plikus said.

This work was supported in part by LEO Foundation grants LF-AW-RAM-19-400008 and LF-OC-20-000611; Chan Zuckerberg Initiative grant AN-0000000062; W.M. Keck Foundation grant WMKF-5634988; National Science Foundation grants DMS1951144 and DMS1763272; and National Institutes of Health grants U01-AR073159, R01-AR079470, R01-AR079150, R21-AR078939 and P30-AR075047. Additional backing came from Simons Foundation grant 594598 and California Institute for Regenerative Medicine Shared Research Laboratory Grant CL1-00520-1.2.

About UCI’s Brilliant Future campaign: Publicly launched on Oct. 4, 2019, the Brilliant Future campaign aims to raise awareness and support for UCI. By engaging 75,000 alumni and garnering $2 billion in philanthropic investment, UCI seeks to reach new heights of excellence in student success, health and wellness, research and more. The School of Biological Sciences plays a vital role in the success of the campaign. Learn more by visiting https://brilliantfuture.uci.edu/school-of-biological-sciences .

About the University of California, Irvine: Founded in 1965, UCI is a member of the prestigious Association of American Universities and is ranked among the nation’s top 10 public universities by U.S. News & World Report . The campus has produced five Nobel laureates and is known for its academic achievement, premier research, innovation and anteater mascot. Led by Chancellor Howard Gillman, UCI has more than 36,000 students and offers 224 degree programs. It’s located in one of the world’s safest and most economically vibrant communities and is Orange County’s second-largest employer, contributing $7 billion annually to the local economy and $8 billion statewide. For more on UCI, visit www.uci.edu .

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Review Article
Open access
Published: 17 February 2021

Functional hair follicle regeneration: an updated review

Shuaifei Ji 1 ,
Ziying Zhu 1 ,
Xiaoyan Sun 1 &
Xiaobing Fu 1

Signal Transduction and Targeted Therapy volume 6 , Article number: 66 ( 2021 ) Cite this article

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Regeneration
Regenerative medicine

The hair follicle (HF) is a highly conserved sensory organ associated with the immune response against pathogens, thermoregulation, sebum production, angiogenesis, neurogenesis and wound healing. Although recent advances in lineage-tracing techniques and the ability to profile gene expression in small populations of cells have increased the understanding of how stem cells operate during hair growth and regeneration, the construction of functional follicles with cycling activity is still a great challenge for the hair research field and for translational and clinical applications. Given that hair formation and cycling rely on tightly coordinated epithelial–mesenchymal interactions, we thus review potential cell sources with HF-inducive capacities and summarize current bioengineering strategies for HF regeneration with functional restoration.

Expansion and characterization of epithelial stem cells with potential for cyclical hair regeneration

Local and systemic mechanisms that control the hair follicle stem cell niche

Deciphering the molecular mechanisms of stem cell dynamics in hair follicle regeneration

Hair follicles (HFs) are a major skin appendage originating from the ectoderm. As a stem cell repository and a hair shaft factory, the HF contributes to remodelling its cutaneous microenvironment, including skin innervation and vasculature. 1 The HF participates in multiple functions, mainly physical protection, thermal insulation, camouflage, sebaceous dispersion, sensory perception and social interactions. In addition, hair in human society greatly affects the quality of life, attractiveness and self-esteem. However, destructive inflammation with various aetiologies and the subsequent replacement of fibres can involve the permanent loss of HFs, which impairs inherent skin function and, especially, psychological well-being. Thus, HF regeneration is in ever-increasing demand and has promising market prospects. HF morphogenesis and regeneration were shown to be dependent on the intensive cooperation of epithelial (epidermal stem cell [Epi-SCs]) and hair-inducive mesenchymal (dermal papilla [DP]) components, also called epithelial–mesenchymal interaction (EMI). EMI is a prerequisite for functional HF formation, regeneration and cycling, mainly through paracrine mechanisms, 2 and has become the theoretical basis of tissue engineering for HF regeneration. Current strategies to regenerate HF in vivo are aimed at simulating EMI, mostly adopting the principle of combining epithelial (Epi-SC and keratinocyte) and mesenchymal (DP cell [DPC] and skin-derived precursors [SKPs]) components. HFs are also a dynamic mini-organ, and their most notable feature is hair cycling (Fig. 1a ), from periods of organ regeneration and rapid growth (anagen) to apoptosis-driven regression (catagen); then, the HF moves back into anagen via an interspersed period of relative quiescence (telogen). 1 The interaction between HF stem cells (HFSCs) and DPCs plays a significant role in the regulation of hair cycling. 3 , 4 The activation, stability and sustainability of hair cycling are considered to be a key factor in achieving the longevity of HF function, but HF loss is often accompanied by the termination and elimination of hair cycling. Thus, the achievement of hair cycling regeneration is important for functional HF regeneration. Although hair transplantation has been widely applied, transplanted hair is not maintained in the long term. Moreover, clinical drugs still fail to meet the patents’ needs and even have drastic side effects. 5 Therefore, there is a need to explore alternative therapeutic solutions capable of generating functional HFs. Current techniques could make it possible to obtain potential cells in vitro (Fig. 1b ), such as DPCs (Fig. 1c ), SKPs, keratinocytes and other stem cells (Fig. 2 ), providing us with a series of cell sources. In addition, the optimization of the culture system also contributes to preserving the HF-inducive ability of potential cells. Based on these findings, we are able to regenerate functional HFs by the transplantation of potential cell mixtures, HF organoid construction in vitro, reprogramming induction and the establishment of a drug delivery system (Fig. 3 ). Here, we will review the potential cell sources and tissue engineering techniques that contribute to HF regeneration. In addition, the limitations and future of functional HF regeneration are summarized.

The process of hair cycling and DPCs in HF regeneration. a Mature and actively growing HFs anchored in the subcutis periodically regenerate by spontaneously undergoing anagen (repetitive cycles of growth), catagen (apoptosis-driven regression) and telogen (relative quiescence), which is termed hair cycling and is a typical characteristic of functional HFs. b Skeleton diagram of potential cells that contribute to regenerating HFs. c iPSCs share similar characteristics with embryonic stem cells in terms of morphology, self-renewal and differentiation capacity, and they can be induced into other potential cells in regenerative medicine. The transformation of fibroblasts into DPCs via lineage reprogramming. Optimization of the in vitro system to preserve the HF-inducive potential and the transplantation of cell-based biomaterials or HF organoids in vivo to regenerate HFs

Keratinocytes and SKPs in HF regeneration. a iPSCs were reprogrammed into keratinocytes, and biomaterials containing a mixture of fibroblasts and keratinocytes were embedded for de novo HF. b Fibroblasts were chemically induced into SKPs. A mixture of SKPs and epidermal stem cells or bioactive peptides was embedded in the hydrogel to regenerate HFs three-dimensionally

Strategies to achieve functional HF regeneration

Potential cell sources and mechanism for HF regeneration

DPCs, a kind of differentiated dermal cell at the base of HFs, 6 originate from blimp1+ fibroblasts (dermal stem cells [DSCs]) during embryonic development. 7 , 8 DPCs have the ability to stimulate epithelial HFSCs and are considered to be a master regulator of HF cycling. Past studies reported that DPCs isolated from rat and guinea pig vibrissae, as well as humans, could also induce HF formation when implanted into recipient non-hairy skin, 9 , 10 which indicates that DPCs could reprogramme non-hairy epidermis to a follicular fate. Subsequently, DPCs, either fresh or after tissue culture expansion, could also reproduce new HFs if placed in proximity to the epithelium. 11 , 12 Based on their strong HF-inducive ability, many attempts to coculture DPCs with other cell types to regenerate HFs have been studied, such as the two-dimensional juxtaposition of other epithelia, 13 cultured epithelial cells, 14 , 15 keratinocytes, 16 , 17 corneal epithelium 18 and amnion epithelium. 19 DPCs can secrete various factors to initiate HF formation by activating skin epithelial stem cells (Epi-SCs), so the mixture of DPCs and Epi-SCs also promotes functional HF regeneration in vivo. 20

DPCs with specific marker molecules possess HF-inducive capacity, including CD133 + DPCs and Versican + DPCs. CD133 + DPCs have been shown to be a specific subpopulation of cells in DPCs, and they can produce Wnt ligands and mediate signalling crosstalk between the mesenchyme and the epithelial compartment, further promoting adult HF growth and regeneration. 21 In addition, Versican + DPCs exhibit the typical characteristics of aggregation growth, 22 on which HF formation is highly dependent. 23 In addition, many functional molecules are involved in the positive regulation of DPC HF-inducive capacity (Fig. 4 ), such as endothelin-1 and stem cell growth factor , 24 insulin-like growth factor-1 (IGF-1) 25 and histidine decarboxylase , 26 but matricellular protein connective tissue growth factor (CCN2) negatively regulates HF regeneration, physiologically curbing HF formation by the destabilization of β-catenin . 27 In wound healing, hedgehog gene activation could shift the dermal fibroblast fate towards DPCs and result in extensive HF neogenesis. 28 Hoxc genes are able to reprogramme DPCs, and a single Hoxc gene is sufficient to activate dormant DP niches and promote regional HF regeneration through canonical Wnt signalling. 29 Monoterpenoid loliolide regulates the HF inductivity of human DPCs by activating the AKT/β-catenin signalling pathway. 30 Although DPCs possess the potential to regenerate HFs, freshly isolated human DPCs are not efficient in regenerating new HFs when they are directly transplanted. 31 To restore their intrinsic properties, three-dimensional (3D) spheres offer a more physiologically relevant system where cell–cell communication as well as microenvironments have been studied. It has been reported that sphere formation increases the ability of cultured human DPCs to induce HF from mouse epidermal cells, 32 in which glucose metabolism 33 and epigenetics 34 may be important regulators. The natural vitamin E form tocotrienol acts upstream of DP formation to induce HF anagen, dependent on the loss of E-cadherin and activation of β-catenin. 35 Pretreatment with 1α,25-dihydroxyvitamin D3 (VitD3) could significantly improve DPC functionality and hair folliculogenesis, which is mediated by the activation of Wnt10b, alkaline phosphatase (ALP) and transforming growth factor β2 (TGF-β2). 36 Consistent with VitD3, platelet-rich plasma has been shown to function in HF regeneration by enhancing DPC proliferation, 37 which may result from the downregulation of MYC, CCAAT/enhancer-binding protein beta and E2F transcription factor-1 gene. 38 Icariin promotes mouse HF growth by increasing IGF-1 secreted by DPCs. 39 Utilization keratinocyte-conditioned medium, 40 coculture with keratinocytes 40 , 41 or the addition of BMP6 42 and basic fibroblast growth factor (FGF) 43 to DPC expansion cultures could preserve their HF-inducive capacity. JAK inhibitor regulates the activation of key HF populations, such as the hair germ, and improves the inductive potential of DPCs by controlling a molecular signature enriched in intact, fully inducive DPs. 44

The regulatory factors of DPC HF-inducive capacity. Glucose metabolism and LncRNA-XIST/miR-424 axis in the regulation of HF-inducive potential of DP spheres

Skin-derived precursors

DSCs are stem cells located in the dermis of the skin. Based on distinct phenotypic properties and different cultural environments, DSCs can be divided into dermal fibroblasts and SKPs. 7 , 45 For instance, DPCs are differentiated dermal cells originating from blimp1 + dermal fibroblasts, 7 while SKPs are derived from Sox2 + follicle-associated dermal precursors. 46 SKPs are defined as DSCs that reside in the adult HF mesenchyme and can be isolated and expanded in vitro as self-renewing colonies. SKPs have the capacity to differentiate in vitro and in vivo into multiple lineages of different progeny. 47 Of note is that SKPs could regenerate the dermal sheath and repopulate DPCs in each growth cycle 48 to serially reconstitute HF when subcutaneously engrafted. 46 There are also various molecules affecting the inductive potential of SKPs. Trichostatin A, a potent and specific inhibitor of a histone deacetylase, could restore the HF-inducive capacity of SKPs by markedly alleviating culture expansion-induced SKP senescence, increasing the expression and activity of ALP and elevating the acetylation level of histone H3. 49 Platelet-derived growth factor (PDGF) could enhance SKP proliferation, increase SKP progeny and improve their HF-inducive capacity, but PDGF deficiency results in a progressive depletion of the stem cell pool and their progeny. 50 Many tentative methods to isolate and cultivate SKPs have also been explored, 51 , 52 particularly in computer-controlled stirred suspension bioreactors, which lead to a greater expansion of viable SKPs. 53 This technique allows a large number of SKPs that share a similar expression profile to that in static culture (fivefold greater than in static culture), and both static and bioreactor condition-derived SKPs are able to induce de novo HFs and repopulate their cellular niches. 53

Epidermis-derived cells

HFSCs are heterogeneous Epi-SCs compartmentalized along the longitudinal axis of HFs. They are divided into quiescent and primed HFSCs. For instance, relatively quiescent HFSCs in the follicular bulge region can serve as a reservoir for transient amplifying cells that are able to produce various cell types during HF regeneration. 54 Primed HFSCs have faster activation dynamics in the secondary hair germ of telogen HF. 55 The activation of primed HFSCs could trigger the subsequent activation of quiescent HFSCs, and the coordination of these two populations could fuel HF regeneration from telogen to anagen. 56 , 57 HFSCs express a panel of transcription factors, including Sox9, Tcf3, Lhx2 and Nfatc1. 57 , 58 , 59 HFSCs derived from a single rat vibrissa via organ culture could reconstitute HFs in vivo, 60 and even aged HFSCs still have the potential to regenerate HFs. 61 HFSCs could also differentiate into epidermal and sebaceous gland lineages, participating in the process of skin wound healing, and thus were considered ideal candidates for cutaneous repair and regeneration. Recent studies have reported that basal keratinocytes also have the capacity to facilitate HF regeneration under induction. Transgenic expression of the hairless gene ( HR ) in progenitor keratinocytes could rescue HF regeneration in Hr(−/−) mice, in which the new HFs resemble wild-type follicles and express markers of early anagen. 62 This process may be linked to the regulation of the precise timing of WNT signalling to HR. 62 , 63 Tuberous sclerosis complex 2 (TSC2)-null fibroblast-like cells grown from human TSC skin hamartomas could also induce neonatal foreskin keratinocytes to form HFs, complete with sebaceous glands, hair shafts, inner and outer root sheath (ORS) cells and the anagen-specific expression of versican, in which the TSC1/TSC2/mTORC1 pathway may play a significant role. 64

Reprogrammed cells

The differentiation of stem cells into adult cells in response to defined factors is an important application of cell reprogramming. Induced pluripotent stem cells (iPSCs) have similar characteristics to embryonic stem cells in terms of morphology, self-renewal and differentiation capacity. They are not only free from ethical issues but also able to be propagated as autologous cells, which can avoid the complication of immune rejection. Thus, reprogramming of iPSCs into potential cells could be an approach to providing cell sources for HF regeneration. Under retinoic acid (RA), an iPSC-derived LNGFR + Thy1 + subpopulation with high proliferation could be induced into DPCs in the DP medium. 65 The mixture of iPSC ectodermal precursor cells in keratinocyte culture medium with RA and bone morphogenetic protein (BMP) could also transform into new DPCs. 66 Intriguingly, iPSCs could also be generated from human DPCs upon lentiviral transfection with Oct4, Sox2, Klf4 and c-Myc. 67 In addition, iPSCs, post-culture on Matrigel, could differentiate into keratinocytes when treated with keratinocyte serum-free media supplemented with all- trans RA and BMP4. 68 Human hair follicular keratinocytes could also be reprogrammed into iPSCs, and keratinocyte-derived iPSCs are further capable of differentiating into keratinocytes, 69 which suggests a novel way to provide a source of keratinocytes. Lineage reprogramming is direct cellular reprogramming, which means that targeted cells could bypass the stem cell stage and convert directly to potential cells. Unlike traditional concepts regarding the epigenetic stability of differentiated cells, direct lineage reprogramming can transform one specialized cell type into another using defined factors, which is a more efficient and promising approach for producing functional cells. Treatment with the combination of FGF2, PDGF and 6-bromoindirubin-3′-oxime (BIO) could chemically transform human dermal fibroblasts into DPCs. 70 SKPs can be produced from healthy adult fibroblasts via lineage reprogramming, and their cryopreservation can largely preserve their properties and produce more significant yields. 71 Another way to rapidly expand SKPs via lineage reprogramming is to expose pre-established dermal fibroblasts to 30-min acid stress prior to isolating SKPs. 72 Acute acidic stress treatment of dermal fibroblast cultures greatly improves SKP isolation, growth, yield and multipotency.

With progress in HF developmental biology and cellular reprogramming techniques, several cells with the potential for HF regeneration have been identified. These results have greatly expanded the seed cell bank for HF regeneration and solved the problem of the lack of a cell source. However, the problems these cell sources have in common are that their potential to regenerate HF fails to be maintained during long-term culture in vitro. In addition, HFSCs are few in number and extremely difficult to obtain, and SKPs in vitro senesce soon when isolated from their physiological environments. 73 In addition, the efficiency of reprogramming by gene editing is still low. The optimization of the culture system in vitro and the improvement of reprogramming efficiency are challenges for HF regeneration. Therefore, we believe that the construction of 3D culture systems that simulate the in vivo environment may provide an alternative approach, similar to hydrogel scaffold-based cell culture, which contributes to maintaining cell proliferation and growth as well as the potential to regenerate HFs. In addition, chemical reprogramming, a new reprogramming technology, is characterized by high security and efficiency. 74 To improve the reprogramming efficiency, the replacement of chemical reprogramming with gene editing has broad prospects in HF regeneration.

Mechanisms for the restoration of HF-inducive capacity

After birth, mature and actively growing HFs eventually become anchored in the subcutis and then undergo hair cycling, periodically and spontaneously undergoing repetitive cycles of growth (anagen), apoptosis-driven regression (catagen) and relative quiescence (telogen). Therefore, the HF is regarded as a dynamic mini-organ. The activation and maintenance of hair cycling is a prerequisite for the functional regeneration of HFs. HFSCs play an indispensable role in maintaining hair cycling. The HFSC population remains largely quiescent during hair growth, but a subpopulation actively proliferates and promotes the production of the new hair shaft under the control of Axin2 expression. 75 At the onset of anagen following stimulation by growth-inducing signals from the DP, primed HFSCs also contribute to new hair shaft production. 76 Under induction by such signalling, primed HFSCs undergo rapid proliferation to fuel the initial stage of hair growth, and then, the quiescent HFSCs undergo a second round of activation that replenishes cells lost at the onset of anagen, finally supporting prolonged growth of the hair shaft. 56 At the beginning of anagen, activated HFSCs migrate from the bulge to the matrix area and become transit-amplifying cells that proliferate and differentiate to form the new hair shaft. 77 Therefore, the coordinated activation of primed HFSCs and quiescent HFSCs is instrumental for the maintenance of hair cycling. The mechanism underlying HFSC homeostasis and hair cycling regulation is a complex molecular controlling process (Table 1 ) that is highly dependent on hormonal action. 78 WNT/β-catenin and BMP signalling are considered to be the core pathways in the regulation of hair cycling. 79

The dynamic characteristics of HFs enable their sustainable and periodic regeneration. We think that the activation and maintenance of hair cycling are indispensable for achieving functional HF regeneration. Past studies have not only led to a better understanding of the molecular mechanisms of hair cycling, which makes it more possible to find the key molecules therein, but also have revealed the complexity of HF dynamic characteristics. Therefore, it is still difficult to discover the key molecular event in hair cycling.

In vivo strategies for functional regeneration of HFs

Cell transplantation and hf regeneration.

Cell-based transplantation without biomaterials is a minimally invasive approach to in vivo HF regeneration. Current cell transplantation mainly involves the transplantation of stem cells or a mixture of epidermal and dermal components. The injection of a mixture containing Epi-SCs and DPCs into nude mice could induce new HFs with the correct histological structures and form a multilayered stratified epidermis containing HF-like structures. 20 Although the new HFs are relatively small, this result proves again that the rearrangement of the EMI and the niches of the potential cells are essential and necessary for HF construction. A mixture of Epi-SCs and SKPs was grafted into excisional wounds in nude mice, and a bilayer structure resembling the epidermis and the dermis formed on the fifth day, followed by de novo HF. 80 In the regeneration process, the SKPs formed DPCs in neogenic HFs and abundant dermal cells in the dermis, and the Epi-SCs formed the epidermis and trunk of the HF. More importantly, this experiment also demonstrates that the PI3K-Akt signalling pathway plays a crucial role in the interactions between Epi-SCs and SKPs and de novo HF regeneration, which may suggest potential therapeutic applications in enhancing hair regeneration. 80 During the hair growth cycle, HFSCs periodically switch between the active and inactive stages to maintain stem cell populations and generate new HFs, while this potential is impaired in aged HFSCs. 81 However, in transplantation assays in vivo, aged HFSCs could still regenerate HFs when supported with the young dermis, while young HFSCs failed to regenerate HFs when combined with the aged dermis, which shows that the ageing skin microenvironment dictates stem cell behaviour and illustrates the dominant role of the niche microenvironment. 61 This research discovered that the HF regeneration potential of aged HFSCs can be rejuvenated by neonatal dermis during in vivo transplantation, providing promising new avenues for regenerative and geriatric medicine. In recent years, for the fully functional regeneration of ectodermal organs, a bioengineered organ germ has been developed by reproducing the embryonic processes of organogenesis, including bioengineered HFs. 82 Bioengineered HF germ could be reconstituted with embryonic skin-derived epithelial and mesenchymal cells and was able to develop histologically correct HFs when ectopically transplanted. The bioengineered HFs not only properly connected to the host skin epithelium by intracutaneous transplantation and reproduced the stem cell niche and hair cycling but also autonomously connected with nerves and the arrector pili muscle at the permanent region and exhibited piloerection ability. 83 Another way to construct bioengineered HF is with pelage and vibrissae reconstituted with embryonic skin-derived cells and adult vibrissa stem cells. After intracutaneous transplantation, this bioengineered HF germ not only develops the correct structures and forms proper connections with surrounding host tissues such as the epidermis, arrector pili muscle and nerve fibres but also shows restored hair cycling and piloerection through the rearrangement of follicular stem cells and their niches, with fully functional hair organ regeneration. 84 It is worth mentioning that the in vivo transplantation of bioengineered HFs also achieves the partial restoration of hair cycling, which is a great step forward for functional HF regeneration.

Cellular reprogramming and HF regeneration

Cellular reprogramming is not only a tool for tissue engineering to enrich potential cell sources for the regeneration of HF but also a participant in physiological de novo HF induction. Secreted proteins (apolipoprotein-A1, galectin-1 and lumican) from embryonic skin conferred upon non-hair fibroblasts the competency to regenerate HF via the activation of IGF and WNT signalling, thereby endowing non-HF skin with the ability to reproduce HFs, which suggests the involvement of cellular reprogramming. 85 Because DPCs and dermal fibroblasts originate from common fibroblast progenitors in the developing embryonic mouse skin and have highly correlated gene expression profiles (96%), 86 adult dermal fibroblasts can be reprogrammed into a neonatal state, with the capacity of inducing ectopic HF formation similar to DPCs through the epidermal activation of β-catenin. 87 Furthermore, treatment with the combination of FGF2, PDGF and BIO in adherent culture followed by suspension culture could induce the generation of DP-like cells from foetus- or adult foreskin-derived fibroblasts. The integration of foetal/adult DP-like cells can be recruited to replenish DP of de novo generated HFs, and the regenerated HF structures were reconstructed in 65% nude mice implanted with foetal DP-like cells and in 70% nude mice with adult DP-like cells. 70 Finally, the combination of MITF, SOX10 and PAX3 could directly convert mouse and human fibroblasts into induced melanocytes, which have the ability to generate pigmented epidermis and HF in vivo when properly integrated into the dermal–epidermal junction. 88 Healed wounds with the loss of HF are usually filled with a large number of fibroblasts, so the exploration of fibroblast-based reprogramming holds great promise for HF regeneration in situ.

Cell-laden biomaterials for the establishment of HF equivalents

Biomaterials are implantable, inactive materials that can replace or repair damaged tissue with high biocompatibility. Biomaterials can create a 3D environment for cell-to-cell interactions, simulating the function of cell niches to a certain extent, and they have been widely used in wound repair and tissue regeneration. 89 The combination of potential cells with biomaterials, such as hydrogels, scaffolds and other self-assembled materials, could contribute to HF regeneration (Figs. 1c and 2 ). For in vivo HF regeneration, a 3D hydrogel with a mixture of epidermal keratinocytes, dermal cells and β-catenin-expressing CD133 + DPCs not only performed better than CD133 + DPCs alone (average of 28 ± 6 HF per field vs. 13 ± 6 HF per field) but also exhibited a more advanced hair cycling stage; 90 an average of 71% of the HFs reached anagen stage III, and 19% reached anagen stage IV in reconstituted skin containing β-catenin-expressing CD133 + DPCs, while 67.5% of the HFs in the control remained in anagen I and II, and only 27.5% reached anagen III. 90 The stable expression of β-catenin could promote the clonal growth of CD133 + DPCs in vitro in 3D hydrogel culture. An alternative strategy to reproduce EMI is to use a collagen-chitosan scaffold (CCS)-based 3D system containing dissociated epithelial cells and DPCs followed by treatment of the CCS with Wnt-CM from Wnt1a + bone marrow mesenchymal stem cells. The results suggested that the cell mixture was able to induce hair regeneration in nude mice, and Wnt-CM can maintain the hair induction ability of DPCs in expansion cultures, which may be associated with the activation of the Wnt/β-catenin signalling pathway. 91 Therefore, how to enhance the HF induction efficiency of cultured human DPCs is a priority in bioengineering for clinical HF regeneration. It has been reported that DPCs retain HF inductivity best when cultured and transplanted as multicellular aggregates, and DP spheroids could form a structure similar to the natural intercellular organization in vivo. 92 Therefore, another strategy is to achieve the scalable fabrication of controllable DP spheroids to regenerate HFs. Scalable production of controllable DP spheroids on polyvinyl alcohol surfaces has high viability and preserves DP characteristics, and at DPC numbers of 5 × 10 3 to 30 × 10 3 cells each, both human and rat DP spheroids are able to induce HF neogenesis. Larger DP spheroids exhibit higher HF inductivity. The researchers developed a method that can be automated for mass production of DP spheroids with controllable size and cell number in a wide range, 93 although the average diameter of regenerated hair fibre did not significantly change with increasing size of the transplanted DP spheroids. Likewise, the hanging-drop approach could also lead to a controllable 3D spheroid model for the scalable fabrication of inductive DP microtissues. That technique is based on surface tension and the interaction between surface tension and a gravity field that causes the convergence of liquid drops. With the converged drops, DP spheroids could endow high-passaged DP microtissues with many similarities to primary DP. Subcutaneous implantation of these microtissues mixed with new-born mouse epidermal cells has achieved reproducible HF induction in the hypodermis of nude mice, and a large amount of extracellular matrix (ECM) components is found in the intercellular space within the DP microtissue, similar to an anagen DP. 94 These models provide the potential to elucidate the native biology of human DP and show promise for the controllable and scalable production of inducive DPCs for future follicle regeneration. Exosomes derived from DP spheroids (3D DP-Exos) are also able to promote the proliferation of DPCs and ORS cells and accelerate anagen onset to influence hair cycling. Local injections of 3D DP-Exos (exosomes) could induce anagen from telogen and prolong anagen in mice. Moreover, DPC spheres treated with Exos could augment HF neogenesis when implanted with mouse epidermal cells, 95 which may be associated with high levels of miR-218-5p in Exos. 96 Cell surface engineering technology also advances HF regeneration by accurate micro/nanoscale control in cell-biomaterial ensembles and DP spheroid formation. Owing to the security and tuneable thickness at the nanoscale, the nanogel could encapsulate a single cell by layer-by-layer (LbL) self-assembly and further form DPC spheroids by physical cross-linking on nanogel-coated cells. LbL-DPC aggregation is akin to that of primary DPCs and has the capacity to restore HF induction potential in vitro and regenerate HFs in vivo. 97 Other biomaterials that contribute to the restoration of HF-inducive ability include human placenta ECM hydrogel, 98 synthesized ECM 99 and a chitosan/polyvinyl alcohol nanofibre sponge with an open-cell cellular structure, 100 which expands the biomaterial libraries for the optimization of the culture environment in vitro to restore the ability of DPCs to regenerate HFs. 3D printing technology for HF regeneration by recapitulating the physiological 3D organization of cells in the HF microenvironment is an innovative biomimetic approach. 101 It permits the controllable self-aggregating spheroid formation of DPCs in a physiologically relevant ECM, the initiation of EMI and further HF formation in human skin constructs. Remarkably, the vascularization of HF-bearing human skin constructs increases graft survival and enables efficient human hair growth in mice. 101 This method represents a novel bioengineering strategy for the feasible generation of hair-bearing human skin constructs entirely ex vivo from cultured human cells, and adaptation of this new technology by hair researchers, hair restoration surgeons and the pharmaceutical industries will have overwhelming implications in the maintenance and regeneration of HFs.

Similar to DPCs, long-term culture could also impair the HF-inducive capacity of SKPs. It is likely that SKPs rely on special environments for their self-renewal and stable gene expression. In tissue engineering, scaffolds are created to mimic environments for stem cells to survive, differentiate and form functional tissue structures. In this regard, scaffolds such as hydrogels and matrix could be candidates to support stem cells for organogenesis and regenerate HFs. 102 , 103 Self-assembling peptide nanofibres are made of natural amino acids and form hydrogels that surround cells in a manner similar to the ECM. RADA16 (Ac-(RADA)4-CONH2) is a representative example of such peptides that has been shown to promote nerve regeneration and wound healing. 104 , 105 A PRG (PRGDSGYRGDS) solution functionalized by mixing with RADA16 promoted the proliferation and migration of periodontal ligament fibroblasts. 106 The self-assembling peptide hydrogels formed by RADA16 and PRG (RADA-PRG) could facilitate the attachment, proliferation and survival of SKPs, ultimately supporting HF neogenesis in vivo. The transplantation of a combination of culture-expanded SKPs and neonatal epidermal cells into RADA-PRG hydrogel resulted in a significantly increased number of neogenic hairs compared to Matrigel and other peptide hydrogels. This may be attributed to the similarity of the properties of these designer peptide nanofibres to those of ECM molecules. 102 In addition, a mixture of culture-expanded Epi-SC and SKPs derived from the adult human scalp in a hydrogel was capable of reconstituting functional HFs, and the mechanisms of the expression of ALP in SKPs in vitro and the maintenance of HF-inducive properties in vivo may be associated with BMP4. 103 More importantly, Epi-SC implanted in wounds in combination with SKPs could also form functional sebaceous glands in association with HFs. Normal human neonatal foreskin keratinocytes were induced to differentiate into several cellular components that compose normal HFs, with the expression of anagen-specific versican when grown on a collagen matrix embedded with TSC2-null fibroblast-like cells or with fibroblasts. 64 Regenerated HFs were complete with sebaceous glands, hair shafts and inner and ORSs. 64

Drug delivery systems for HF construction

Drug delivery systems consist of molecules with pharmacological activity modified into advanced materials, which have been widely used in skin wound treatment. Currently, it has been reported that many drug delivery systems could promote wound healing as well as HF regeneration. Newly developed multidomain peptide hydrogels have exhibited regenerative potential in a diabetic wound healing model, resulting in wound closure, accelerated HF regeneration and a greater average number of HFs at both the edge and the centre. 107 Multifunctional Zn-doped hollow mesoporous silica/polycaprolactone electrospun membranes exhibit excellent antibacterial activity for wound healing and are ~20 times as likely to regenerate HFs as the control. 108 Most excitingly, the treatment of deep second-degree scalding injuries with human erythropoietin (EPO) to, whether by the local subcutaneous injection of nanosized rhEPO (recombinant human EPO)/infusion pumping or the topical application of rhEPO gel, achieved excellent skin repair with conical and HF structures, which was related to the combined expression of EPO receptor and β-subunit receptor. 109 , 110 A novel fibrous membrane (P/Qu/Cup, P: PCL, Qu: Quercetin, Cup: cuprorivaite, CaCuSi 4 O 10 ) containing quercetin-copper (Qu-Cu) chelates was fabricated by using quercetin and highly bioactive bioceramic (CaCuSi 4 O 10 ) incorporated in PCL/gelatine electrospun fibres. The fibrous membrane can effectively release Qu and Cu ions to induce the proliferation, migration and differentiation of skin- and HF-related cells, and the Qu, Cu ions and Si ions released from the composite membrane revealed synergistic activity to stimulate HF regeneration and wound healing in burned skin. 111 However, drug delivery systems mainly contribute to wound repair, accompanied by the acceleration of wound-induced HF neogenesis (WIHN). WIHN is a regenerative phenomenon separate from physiological regeneration, as its cellular origin is not from the HFSCs in the bulge at the wound edge. In WIHN, a fully functional follicle can regenerate in the centre of a full-thickness wound with a large enough size, and the cellular origin of this process is similar to an embryonic process. The neogenic follicles have similar functions to embryonic HFs, which also have a growth cycle. 63 Currently, there are few studies about drug delivery systems for HF regeneration alone outside the wound environment. However, because of their controllability, targeted delivery, sustained release and even intellectuality, we think drug delivery systems hold great promise for HF regeneration in the future.

Organoid technology and HF replacement

An organoid is defined as a 3D structure grown from organ-specific stem cell types. It can recapitulate key aspects of in vivo organs and avoid many of the disadvantages associated with cell lines. 112 HF organoids can be established from skin stem cells or a mixture of dermal and epidermal components. DP spheroids encapsulated by silk-gelatine hydrogel and HF keratinocytes as well as stem cells could be used to construct in vitro HF organoids. These organoids show enhanced DPC-specific gene expression and ECM production, and their structural features and cell–cell interactions are similar to those of in vivo HFs. 113 This simple in vitro DP organoid model system has the potential to provide significant insights into the underlying mechanisms of HF morphogenesis and distinct molecular signals relevant to different stages of the hair cycle and hence can be used for the controlled evaluation of the efficacy of new drug molecules to induce HF regeneration. To date, in vitro skin derivation strategies have focused on first generating keratinocytes and fibroblasts from iPSCs in separate cultures and then combining the two types of cells to form a skin-like bilayer. A major challenge is how to realize the synchronous construction of its appendages. Under initial treatment with the TGF-β inhibitor SB431542 (SB) and recombinant BMP4 and subsequent treatment with FGF2 (FGF) and a BMP inhibitor LDN-193189 (LDN), a homogeneous population of mouse pluripotent stem cells and constituting epidermal and dermal layers in a 3D culture formed skin organoids with a cyst conformation, in which HFs were spontaneously produced de novo. However, the new HFs entered catagen and degenerated during long-term culture. 114 These results suggest how skin organoid structures can be generated de novo without the use of embryonic tissue or undefined media, which will be useful for studying the minimal cellular and microenvironment requirements for HF induction. Scalp-derived dermal progenitor cells mixed with foreskin-derived Epi-SCs at a 2:1 ratio could aggregate in suspension to form a large number of HF organoids, and the dermal and epidermal cells self-assembled into distinct epidermal and dermal compartments. The addition of recombinant WNT3a protein to the medium enhanced the formation of these aggregates, and the transplantation of these organoids in vivo achieved HF formation. 115 Finally, a 3D integumentary organ system (IOS) obtained by the self-assembly of mesenchymal and Epi-SCs from iPSCs using the clustering-dependent embryoid body transplantation method also regenerated fully functional HF organoids. 116 After transplantation into nude mice, the HF organoid in that system could form proper connections to the surrounding host tissues, such as the epidermis, arrector pili muscles and nerve fibres, without tumorigenesis, and show appropriate hair eruption and hair cycles, including the rearrangement of follicular stem cells and their niches. 116 These findings reveal the generation of a bioengineered 3D IOS from iPSCs, including appendage organs such as HFs and sebaceous glands, with appropriate connections to surrounding tissues, which significantly advances the technological development of the bioengineered 3D IOS and its potential applications, including an in vitro assay system, an animal model alternative and bioengineered organ replacement therapy.

The transition from traditional culture to 3D culture constitutes excellent progress in HF regeneration. 3D culture enhances the proliferation and HF regeneration ability of potential cells, and a mixture of epidermal (Epi-SC) and dermal (SKP and DPCs) components in a 3D system simulates the characteristics of EMI, especially organoid technology and 3D printing technology. In 3D culture, regenerated HFs in vivo not only connect appropriately to surrounding host tissues but also undergo hair cycling activation. However, some problems are less thoroughly addressed. How long can the regenerated HFs last? Can the regenerated HFs go through full hair cycling? Will HF regeneration-induced hair be superior to transplanted hair? We think these are key questions and important challenges in functional HF regeneration.

Achievements, limitations and future perspectives

Much progress has been made in the developmental biology and regeneration of HFs. (1) A variety of cells with the potential to regenerate HFs have been identified, including DPCs, SKPs, HFSCs, keratinocytes and reprogrammed cells (iPSCs and fibroblasts), which provide a wide range of cell sources for HF regeneration. (2) We have gained a more comprehensive and in-depth understanding of the hair cycling-related mechanism, which provides the biological basis for finding key molecules to initiate and sustain the hair cycle. (3) Optimization of the in vitro culture system and the construction of a 3D culture environment could overcome the loss of the ability of potential cells to proliferate, self-renew and regenerate HFs caused by 2D culture. (4) The transplantation of a mixture of epidermal and dermal components, such as cell-based transplantation with or without biomaterials and HF organoids, could simulate EMI to a certain extent and successfully induce new HFs with the correct structure in vivo. (5) The HF organoid is a model for the exploration of mechanisms of HF morphogenesis and drug research to reproduce hair. (6) Drug delivery systems are characterized by strong controllability and high security, and they can promote wound healing accompanied by HF regeneration.

Since it is an architecturally and functionally complex organ, the HF is much more difficult to regenerate or reconstruct than many other organs. Due to this limitation, HF regeneration is still far from clinical transformation. (1) The sources of potential cells are still poor, largely because of cell ageing in vitro culture and inefficient reprogramming, so there is still a need to optimize the in vitro culture system. (2) The mechanism of hair cycling is very complex, and it is extremely difficult to identify the key molecules. (3) Current strategies simulating EMI are still insufficient. Both cell transplantation and organoid architecture lack the microenvironment of connective tissue, blood vessels and immune cells, which is still quite different from the physiological environment of normal tissues and organs. (4) It is unknown how many new HFs can be regenerated from biomaterials and tissue engineering. Do they allow other essential cells to be recruited to the new follicle? If so, do the attracted cells have the ability to affect organogenesis overall? 5) The cellular reprogramming techniques that contribute to HF regeneration still have low efficiency in vitro. (6) The 3D regeneration of HFs depends on biomaterials that need better external security, controllability and internal stability. Ideal biomaterials need to be safe and nontoxic. Under normal metabolism in the body, they can be kept in a stable state without biological degeneration, and the metabolism or degradation products are harmless and easily metabolized. (7) Whether the regenerated HFs function normally and how long they can last in vivo are less mentioned in past studies.

In summary, at the current stage, various attempts are only imitating a partial structure and/or function regeneration of HFs. The combination of different technologies and methodologies will hopefully lead to new progress. For example, the creation of transplantable HFs that closely mimic the structures and functions of native tissue may be accomplished by combining organoid technology with a drug delivery system. Depending on the controllable release of the relevant factors in hair cycling, such as WNT or BMP, hair cycling activation and maintenance of HF organs may be achieved. We also need to continue to optimize the in vitro culture systems of potential cells and look for more efficient reprogramming techniques, such as chemical reprogramming induced by small molecules or genetic reprogramming of genes delivered by biomaterials. Finally, we want to reiterate that, based on existing work, it is worth considering whether the achievement of the activation and maintenance of hair cycling in regenerated HFs could be the heart of the next phase.

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Acknowledgements

This work was supported, in part, by National Key Research and Development Plan (2018YFC1105704, 2017YFC1103304, 2016YFA0101000, 2016YFA0101002), the National Nature Science Foundation of China (81871569, 81830064, 81721092), the CAMS Innovation Fund for Medical Sciences (CIFMS, 2019-I2M-5-059) and the Military Medical Research and Development Projects (AWS17J005, 2019-126).

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Shuaifei Ji, Ziying Zhu, Xiaoyan Sun & Xiaobing Fu

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S.J. conceived and drafted the manuscript. S.J. and X.S. discussed the concepts of the manuscript. S.J. and Z.Z. drew the figures and summarized the tables. X.S. and X.F. approved the version to be submitted.

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Ji, S., Zhu, Z., Sun, X. et al. Functional hair follicle regeneration: an updated review. Sig Transduct Target Ther 6 , 66 (2021). https://doi.org/10.1038/s41392-020-00441-y

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SCUBE3: New Molecule Discovered That Strongly Stimulates Hair Growth

Scube3 has been found to be a potential therapeutic option for treating androgenetic alopecia..

A signaling molecule known as SCUBE3, which was discovered by researchers at the University of California, Irvine , has the potential to cure androgenetic alopecia, a prevalent type of hair loss in both women and men.

The research, which was recently published in the journal Developmental Cell, uncovered the precise mechanism by which the dermal papilla cells, specialized signal-producing fibroblasts found at the bottom of each hair follicle, encourage new development. Although the critical role dermal papilla cells play in regulating hair growth is widely established, the genetic basis of the activating chemicals involved is little understood.

“At different times during the hair follicle life cycle, the very same dermal papilla cells can send signals that either keep follicles dormant or trigger new hair growth,” said Maksim Plikus, Ph.D., UCI professor of developmental & cell biology and the study’s corresponding author. “We revealed that the SCUBE3 signaling molecule, which dermal papilla cells produce naturally, is the messenger used to ‘tell’ the neighboring hair stem cells to start dividing, which heralds the onset of new hair growth.”

For mice and humans to effectively develop hair, the dermal papilla cells must produce activating chemicals. Dermal papilla cells malfunction in people with androgenetic alopecia, drastically lowering the typically plentiful activating chemicals. For this study, a mouse model with excessive hair and hyperactivated dermal papilla cells was created. This model will help researchers learn more about the regulation of hair growth.

“Studying this mouse model permitted us to identify SCUBE3 as the previously unknown signaling molecule that can drive excessive hair growth,” said co-first author Yingzi Liu, a UCI postdoctoral researcher in developmental & cell biology.

Further tests validated that SCUBE3 activates hair growth in human follicles. Researchers microinjected SCUBE3 into mouse skin in which human scalp follicles had been transplanted, inducing new growth in both the dormant human and surrounding mouse follicles.

“These experiments provide proof-of-principle data that SCUBE3 or derived molecules can be a promising therapeutic for hair loss,” said co-first author Christian Guerrero-Juarez, a UCI postdoctoral researcher in mathematics.

Currently, there are two medications on the market – finasteride and minoxidil – that are approved by the Food and Drug Administration for androgenetic alopecia. Finasteride is only approved for use in men. Both drugs are not universally effective and need to be taken daily to maintain their clinical effect.

“There is a strong need for new, effective hair loss medicines, and naturally occurring compounds that are normally used by the dermal papilla cells present ideal next-generation candidates for treatment,” Plikus said. “Our test in the human hair transplant model validates the preclinical potential of SCUBE3.”

Reference: “Hedgehog signaling reprograms hair follicle niche fibroblasts to a hyper-activated state” by Yingzi Liu, Christian F. Guerrero-Juarez, Fei Xiao, Nitish Udupi Shettigar, Raul Ramos, Chen-Hsiang Kuan, Yuh-Charn Lin, Luis de Jesus Martinez Lomeli, Jung Min Park, Ji Won Oh, Ruiqi Liu, Sung-Jan Lin, Marco Tartaglia, Ruey-Bing Yang, Zhengquan Yu, Qing Nie, Ji Li and Maksim V. Plikus, 30 June 2022, Developmental Cell. DOI: 10.1016/j.devcel.2022.06.005

UCI has filed a provisional patent application for the use of SCUBE3 and its related molecular compounds for hair growth stimulation. Further research will be conducted in the Plikus lab and at Amplifica Holdings Group Inc., a biotechnology company co-founded by Plikus.

The study team included health professionals and academics from UCI, San Diego, China, Japan, Korea, and Taiwan.

The study was funded by the LEO Foundation, the Chan Zuckerberg Initiative, the W.M. Keck Foundation, the National Science Foundation, the NIH/ National Institutes of Health , the Simons Foundation, the National Natural Science Foundation of China, the Training Program of the Major Research Plan of the National Natural Science Foundation of China, and the Ministry of Science and Technology of Taiwan.

Crowding causes internal cell structure alignment, bioengineers develop deformability cytometer to help diagnose disease, papupuncture offers long-lasting pain relief, cost-effective 3-d rna modeling technique, cfp mturquoise2 shines bright, researchers use microfluidic device to monitor sickle cell disease, researchers induce magnetism to a non-magnetic organism, ucla discovery suggests a mechanism and design principle for the engineering of tissue, researchers study metabolic errors and their effect on dna, 49 comments.

New molecule that helps people: first things first – patent it so that a small number of people can profit greatly from it at the expense of the majority! Patents need two urgent changes:

1. in the modern world, they need to be greatly shortened. 3-5 years is more than enough

2. nobody should be allowed to patent a compound that people make in their own bodies

If funding was provided by the the National Science Foundation (of the US), then by law the findings/formulas/devices cannot be proivately patented.

Prove me wrong.

https://en.wikipedia.org/wiki/Bayh-Dole_Act

you are right if funding for any scientific endevour is provided in any way by the us goverment then they own it and will be the ones to profit and given the number of such projects it is a small miracle that the us defecit continues to rise as the ammount of money they should be getting should more than offset the debt but thier is no such thing as a poor politician.

The guy in the video at the top of the article clearly has a fully healthy head of hair. Seems pretty bogus to me.

Absolutely. He has a perfectly formed buzz cut and the time-lapse merely shows it growing back out. Brazenly bogus claim.

Here here. First name I see and recognize is Zuckerberg. Must they own everything?

The Zuckerberg Chan Initiative is a philanthropic organization funded by Mark Zuckerberg and his wife Patricia Chan.

First name I see and recognize is Zuckerberg. Must they own everything?

I would love to know the effects of PRP on hair activation. I don’t believe it’s as available as treatment because of price, but it’s not daily and produces wonderful results. There’s other options/serums also to be injected or microneedled in the scalp. This can be done in tandem with current topicals. So when I say I would like to know, I mean conversely… the curiosity to regulate hair stopping. Sincerely, your fuzzy friend

And once it’s available to the public, we can purchase it for an overly high price, monthly subscriptions etc… and pretty much not be able To afford it. Isn’t that wonderful.

How about figuring out how to locally shut off production of SCUBE3 as well for women with PCOS and other conditions as well as trans women and non-binary people to get rid of facial hair?

Grace X, funding by a charitable foundation in the pursuit of knowledge is quite different than one person behind that foundation owning that idea. This is now paying it forward than scooping up profits.

Every couple of years you see these articles, then you hear nothing. There will never be a cure!

The Zuckerberg Chan Initiative is a philanthropic organization funded by Mark Zuckerberg and his wife Patricia Chan

I’m getting major “latisse” vibes from this. That had major and permanent disfiguring side effects that no one paid attention to until it had already been patented and released to market. Will this be similarly hiding a horrific side effect? Also, patenting biologically occuring chemical compounds shouldn’t be legal. They don’t want to help people, they just want money.

Keep my wife’s condition off yo f&cking ARTICLE

I am not a scientist or doctor or anything else like that but the human body has its own ability to stop peoples hair from falling out and to regrow and even has the ability to regrow hair thicker longer in in places that you don’t even want it to grow up and the reason that I know this is because of one occasion about 25 years ago my left hand was cut wide open from the middle of my ring finger and my pinky straight across the top of my hand almost to my thumb knuckle and it was actually filleted open only the skin in the healing process after getting stitched back up a couple of weeks later my hand started growing hair like a wolf man growing so much being thicker and longer and spreading across my hand in more volume and in places that he didn’t ever grow before I actually had to cut the hair with a pair of scissors because it was getting so long I asked the doctor why this was happening and he said that the traumatic experience to my hand I sent my body into a survival mode and sent all of its soldiers to that hand into that wound to help heal it and protect it from bacteria and infection that is why the hair was growing so sick in so long and spreading around my wound on my hand we had never been before because it was protecting its own self and healing its own self and fighting off bacteria it’s own self find out what properties and what proteins are that the human body produces naturally to cause this and that’s exactly how baldness in women and men can be stopped whether it be naturally or or due to another illness or even an outside cause like chemotherapy the body can heal itself and hair loss is a wound to the body that it has its own Natural serum to accomplish This. Another words there’s no need for man-made chemicals or that you would apply to your place of hair loss and end up having to indefinitely take this same medication that was man-made for the rest of your life because if you did stop taking it all of the hair that you just regroup including all of the hair that is being subjected to this chemical will all fall out.

Punctuation is your friend, John.

Great! My ears and back and inner nose and pubic Himalayas thank the scientists. So do the boys at Harry’s Razors!

Soon available in a cookie form. Called Scube snacks.

I have been suffering from alopecia totalis for 8 years. My hair was 3 feet long thick wavy and white, then it all fell out in 3 months time. I went through a year of cortisone injections to my scalp. It help a tiny bit. The hair I have now is very thin and it has only grown about 8 inches. The front is so thin I only wear headscarves in public. This would be a godsend for my self esteem not to mention getting to shed the damn headscarves!

Ask a rheumatologist for a sample bottle of Xeljanz or Rinvoq. Alopecia Totalis is likely autoimmune, and those medications inhibit enzymes that attack your body. Pfizer and AbbVie reps hand out sample bottles to rheumatologists and medical (not cosmetic) dermatologists like Halloween candy. They’re off-label and not covered by insurance for AT, but maybe your doc will “find” (wink, wink) that you have RA or PsA as well, which insurance will pay for.

I hope that really work and the side efect not be other than help you grow hair and then give you erectal disfuntion I mint you get hair and then loose you manhood

Finesteride is a very dangerous drug with serious side effects that can ruin sex drive (and even seems able in some cases to shrink penile tissue) for years or sometimes it seems for life. The company knows it but won’t stop selling it. Do your research before trying this as a solution to hair loss.

I would like a gallon, please.

How do I get these for my sons…young but balding

How can I grow my I always cover my head because of bad hairlosss

Investigate Ebola or covid you learned asinine person. No one cares about baldness when you are in the coffin.

Go eat cow dung, you asinine fool.

Investigate Ebola or covid you learned asinine scientist fool. No one cares about baldness when you are in the coffin.

Hmm. I thought you can’t patent naturally occurring substances. But may be the patent is for use. But then again a new intended use does not make it patentable. They may or may not be able to get a patent for it.

Weird that participants in the study are scientists from China…AND Taiwan. F*** the Chinese lose their s**t at the mear mention of Taiwan.

>2. nobody should be allowed to patent a compound that people make in their own bodies

Then there should be an alternative document that gives a time-limited sole right to profit from the results of research and investment, in which case the law would decide this will not be deemed as ownership of nature (the thought of which sets some people off)

Grammar Both drugs are not universally effective is poor usage. It is ambiguous at best and erroneous at worst. You are stating that one drug is effective while the other is not. Correct phrasing is that neither drug is universally effective. Basic proper English has become a victim of technology.

And did they mention that this same molecule also stimulates lung cancer cells?

“Signal peptide-CUB-EGF-like domain-containing protein 3 (SCUBE3) is a secreted glycoprotein that is overexpressed in lung cancer tumor tissues and is correlated with the invasive ability in a lung cancer cell line model. These observations suggest that SCUBE3 may have a role in lung cancer progression.” (Wu, et al. 2011)

https://pubmed.ncbi.nlm.nih.gov/21441952/

References: Wu, YY., Peck, K., Chang, YL. et al. SCUBE3 is an endogenous TGF-β receptor ligand and regulates the epithelial-mesenchymal transition in lung cancer. Oncogene 30, 3682–3693 (2011). https://doi.org/10.1038/onc.2011.85

Some people in the comments seem to think this is ready for human trials. No human trials have been done yet. Once more animal trials are done then they will seek approval for human trials if it is safe to proceed. I agree that this should only get a limited time to solely profit from their research, consisting of 3 to 5 years after approval for human use. It will be years before this is ready for human use though. As a balding male, I want it sooner if safe, but I understand the need for rigorous safety trials.

Who cares. Im sexy with no hair. This popped up on google, of course i clicked. Its interesting. I understand the emotional amd psychological stress hair loss causes. Mine fell out at 20. But i didnt care, shaved it and kept livimg my life. If someone didnt like me bald, their loss. Didnt stop me from getting a smoking hot wife, six figure job, multiple degrees, and accomplishing a multitude of goals. I focused on my physique because it was my passion. If you are worried about gow you look, first step get on the scale. Overweight (probably) stop eating crap. Scrawny physique, well if you dont like it eat better and lift. So much we can easily control yet people aim for hair? Its dumb. Teeth i understand, hair i do not. People spens millions on hair replacement. Wouldnt you rather have a boat or sweet car or i dont know more retirement? Hair…gimme a break. Embrace the dome. Be confident in other areas or create that confidence other ways. Moreover, this is science? Why arent they dedicating these resources and efforts to cancer? Seems less selfish and vain to me. But what do i know, im just a baldy, jacked 40yo.

Simple solution to haor loss- Locate and tweak the gene that causes wild hair growth in/on my ears, eyebrows, and in my nose. As I get older the top goes and the random grows.

“2. nobody should be allowed to patent a compound that people make in their own bodies”

Insulin would like to have a word with you.

She asks me why… I’m just a hairy guy…

Some people here seem to think that scientists should spend years educating themselves and work for nothing to “help” humans by discovering medicines to improve disease outcomes.

Likewise for the pharmaceutical companies who they believe are evil for wanting to make a lot of money.

I say go on make some money and bring us effective treatments for baldness for cancer for whatever. The market will pay what it’s prepared to pay.

Pharmaceutical companies have to cover the losses for all the hard work trying to find treatments that end up a failure.

So I have no problem paying someone for their work. The higher salary scientists make the more talent will be drawn into the field. I say bring it on charge what you can. If it’s really important to human health governments will step in to subsidise medicines. Here in Australia we have seen this happen with many medicines including the marvelous cancer immunotherapy drugs that have heralded the future of cancer care.

As for the guy who said forget about hair loss and shave your head. Well not everyone looks so good shaved plus there’s nothing wrong with wanting to wear a full set of hair which also protects your scalp skin from developing skin cancer.

I’ve had two fue transplants and it doesn’t cost that much. An average new car costs more and you’ll get way more satisfaction out of a full head of hair.

I look good with my head shaved or with a full head of hair and I have the option.

I am eagerly waiting for the positive results as I am one of the hair loss patients. Pls help. Loosing hair makes me loose my confidence.

How can I be a patient in this study in SCUBE3: New Molecule That Strongly Stimulates Hair Growth? I am willing to test it on me thank You

Where can I get this from…how much diss it cost???

When will this become avaible…

when will this be ready for use?

Save my name, email, and website in this browser for the next time I comment.

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Hair growth is largely impacted by genetics, but other factors can affect how long and strong your strands are. While hair grows naturally in a cycle, it may be possible to support even quicker hair growth with scalp and hair health products, lifestyle adjustments, and gentle hair care habits.

This article provides an overview of effective strategies for promoting the hair growth process.

Anastassiya Bezhekeneva / Getty Images

Naturally Stimulating Hair Growth (Without Supplements)

While genetics plays a role in hair growth, research suggests various methods may support the growth of longer strands—without using additional supplements or nutrients. Studies show that lifestyle changes, topical hair treatments, and a gentle hair care routine may stimulate hair growth.

Many of these tactics rely on improving circulation and blood flow to the scalp. At least in theory, improved scalp blood flow creates a healthy environment for hair follicles to grow and hair to become longer, thicker, and stronger.

Other tactics involve eating well, stressing less, and cutting back on harmful habits like smoking to help naturally accelerate hair growth.

Stimulating Hair Growth With Supplements

Nutrients are an essential part of hair growth. They can help regulate the hair growth cycle and support overall scalp and body health.

If your hair isn't growing as fast as you'd like, talk to a healthcare provider about possible nutritional deficiencies. Having a deficiency diagnosed with a blood test is important. Taking excessive supplements without a deficiency can be harmful. It is safer to take a multivitamin than a single-nutrient supplement.

Various supplements are available that include key nutrients for promoting hair health. Supplementing with omega fatty acids , zinc , vitamin E , and pumpkin seed oil can potentially help treat hair loss and also encourage healthy hair growth . Some other nutrients you may want to look for are iron and biotin .

At least one study has highlighted that regularly taking supplements with omega-3 fatty acids, omega-6 fatty acids, and antioxidants can promote thicker hair and less hair loss.

Supplements aren't regulated by the Food and Drug Administration (FDA) in the same way that medications are in the United States. Check with a healthcare provider before trying one out to ensure you're not getting too much of a particular vitamin or nutrient.

Average Cycle of Hair Growth

Hair grows in a four-phase cycle , which is:

Anagen : The growth phase
Catagen : The regression phase
Telogen : The rest phase
Exogen : The shedding phase

The average scalp contains around 100,000 hair follicles—and it's normal to lose about 100 hairs every day.

It usually takes about a month for your hair to grow roughly one-half inch. In general, hairs continue growing for about six years before falling out—then new hairs will grow back in their place.

Types of Hair Growth Self-Care

You can take different measures and try different products and treatments to support hair growth.

A hair or scalp serum is a topical treatment that promotes healthy hair growth. A serum is a liquid applied directly to the scalp and hair.

A variety of products is available. Look for one with nutrients that are hydrating without leaving a greasy or oily residue. Follow the directions on the product, such as applying it at night to allow the ingredients to work while you sleep.

Certain shampoos may help address overall hair health, potentially helping your strands get longer and stronger.

Look for moisturizing and thickening shampoos, which can help coat strands with supportive ingredients, strengthening your locks. They can make hair appear thicker and fuller while reducing hair breakage.

Dandruff Products

Shampoos and topical products targeting dandruff may also help promote hair growth.

For example, dandruff shampoos with zinc pyrithione, salicylic acid, sulfur, selenium sulfide, ketoconazole , and coal tar can control dry, flaky skin on the scalp. They also help prevent the itching and scratching that can worsen hair loss —allowing the hair follicles to focus on hair growth and strength.

When dry skin and oil build up on the scalp, it doesn't make for an optimal environment for healthy hair growth.

Trying a scalp scrub that helps gently exfoliate the surface while improving moisture and nourishment can be a simple step in your hair care routine. You may use this type of product as needed before conditioning your hair in the shower.

Scalp or Hair Oils

Applying an oil-based product directly to the scalp has been shown to improve the scalp's condition. This, in turn, can promote healthy hair growth and cut back on hair loss caused by stress.

That said, many different types of hair oil products are on the market, and there's not a one-size-fits-all ingredient that's been scientifically proven to produce hair growth results. If you go this route, select a formula that works well with your hair and scalp type and any skin sensitivities you may experience.

Medicated Topical Treatments

An over-the-counter (OTC) medicated topical treatment known as Rogaine (minoxidil) is commonly recommended by healthcare providers to promote hair growth and enhance hair thickness and density.

When applied to the scalp, minoxidil is believed to widen blood vessels, promoting increased blood flow to hair follicles. This improved circulation is thought to stimulate hair growth and is often used to address conditions such as androgenetic alopecia , commonly known as pattern baldness.

Natural or Essential Oils

Certain essential oils have been shown to help promote hair and scalp health.

Because of antibacterial and antifungal properties, many essential oils like tea tree oil are effective for targeting conditions like dandruff or scalp eczema . This keeps the hair and scalp healthy and moisturized, supporting an optimal environment for hair to grow.

Some studies have shown certain essential oils like rosemary oil to be as effective as medicated topical products for regrowing hair in certain cases. You may want to try other nutrient-rich oils—like coconut oil, argan oil, and olive oil—that have moisturizing fatty acids that can support a well-nourished scalp.

Because certain essential oils—particularly when used in large doses—may cause allergic reactions or other side effects, it's a good idea to perform a small patch test or ask a healthcare provider before trying it out.

Herbal Remedies

Phytochemicals (natural compounds produced by plants) found in several different herbs are a promising option for hair growth.

Some studies and anecdotal evidence have shown that using herbs like rosemary water as a hair tonic or wash can prompt the growth of hair without the added chemicals or toxins that other products may contain. A theory is that herbs might encourage blood flow to the scalp, which reduces inflammation and supports a healthy environment for hair growth.

Various herbal water recipes are available online. Be sure to test for allergic reactions or consult a healthcare provider with any questions.

Castor oil products have also been making the rounds as popular methods for adding thickness and length to hair. High in vitamin E and a certain type of fatty acid, castor oil may help promote scalp circulation—contributing to healthier, stronger, and shinier hair.

Like other scalp oils, castor oil typically is massaged into the scalp and left on overnight to help boost hair growth. Note that there isn't direct scientific evidence supporting the use of castor oil for hair growth, so check with a healthcare provider before adding this to your hair care routine.

Scalp Massagers

Research suggests that using a scalp massage device can help promote hair strength, thickness, and growth. This is due to the way that pressure on the scalp positive impact on the genes in the scalp's skin cells.

One study found that regular use of a scalp massage device over a period of time increased the activity of genes linked to hair growth—and decreased the activity of genes linked to hair loss. While a scalp massaging tool may be a great way to get the job done, experts theorize that a manual (using your hands) massage may be just as beneficial.

Light Therapy Devices

Certain types of light therapy may encourage hair growth and cut down on hair thinning.

Using red or blue light devices at home seems to trigger scalp cells to improve blood supply, reduce inflammation, and regenerate the hair. Some studies have found that light therapy was able to significantly increase hair density after several weeks of use.

At-home tools are available for purchase, though using an in-office device or a light therapy session performed by a healthcare provider may lead to better results.

Collagen, a naturally occurring protein in the body, helps support skin, tissues, joints, and bones. Evidence is mixed on whether it directly supports hair health, but collagen in supplement, liquid, or powder forms may be worth trying.

Certain studies have shown that taking collagen peptides may also help support hair growth, potentially increasing hair follicles and improving hair thickness. In addition, at least one other study found that taking a product containing collagen, peptides , lipids , and hyaluronic acid combined made for softer, shinier, and healthier hair after several weeks.

Still, discuss with a healthcare provider whether adding collagen to your daily routine is right for you.

Prescription Oral Medications

Sometimes, a healthcare provider may recommend a prescription medication treatment to help with hair growth.

Oral medications like Propecia (finasteride), typically prescribed for male hair loss, can work by blocking hormones linked to hair loss. Aldactone ( spironolactone ) is generally prescribed for female hair loss and can help regulate hormones responsible for hair thinning.

Because these products support hair regrowth for certain health conditions or situations, you'll need to work with a dermatologist (a physician specializing in conditions of the skin, hair, and nails) on a specific treatment plan.

What Doesn't Promote Hair Growth

To keep hair healthy and strong, experts recommend avoiding certain lifestyle risk factors. For example:

Cut down on the use of hot tools like curling irons and flat irons, as heat can weaken strands.
Stay away from tight hairstyles , which can pull on hair and potentially lead to permanent hair loss.
Stop smoking to cut down on inflammation throughout the body, which can promote hair loss.
Try to limit stress, which can be a trigger for hair loss

A Word From Verywell

Regardless of the type of scalp or hair treatment, it can take three to six months for the products to work and to begin to see hair growth.

While there's no one-size-fits-all routine for speeding up hair growth, several different methods may contribute to a healthier scalp and strands. Options include a variety of products, tools, nutrients, medications, and hair care techniques that may be beneficial for enhancing hair strength, regrowth, and thickness.

Always check with a healthcare provider for medical treatment if you notice abnormal hair loss or hair thinning.

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Gokce N, Basgoz N, Kenanoglu S, et al. An overview of the genetic aspects of hair loss and its connection with nutrition . J Prev Med Hyg . 2022;63(2 Suppl 3):E228-E238. doi:10.15167/2421-4248/jpmh2022.63.2S3.2765

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Le Floc'h C, Cheniti A, Connétable S, Piccardi N, Vincenzi C, Tosti A. Effect of a nutritional supplement on hair loss in women . J Cosmet Dermatol . 2015;14(1):76-82. doi:10.1111/jocd.12127

Drake L, Reyes-Hadsall S, Martinez J, et al. Evaluation of the safety and effectiveness of nutritional supplements for treating hair loss: a systematic review . JAMA Dermatology . 2023;159(1):79-86. doi:10.1001/jamadermatol.2022.4867

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Ashique S, Sandhu NK, Haque SN, e tal. A systemic review on topical marketed formulations, natural products, and oral supplements to prevent androgenic alopecia: a review . Nat Prod Bioprospect . 2020;10(6):345-365. doi:10.1007/s13659-020-00267-9

Trüeb RM, Henry JP, Davis MG, Schwartz JR. Scalp condition impacts hair growth and retention via oxidative stress . Int J Trichology . 2018;10(6):262-270. doi:10.4103/ijt.ijt_57_18

Suchonwanit P, Thammarucha S, Leerunyakul K. Minoxidil and its use in hair disorders: a review . DDDT . 2019;13:2777-2786. doi:10.2147/DDDT.S214907

Kairey L, Agnew T, Bowles EJ, Barkla BJ, Wardle J, Lauche R. Efficacy and safety of Melaleuca alternifolia (tea tree) oil for human health—a systematic review of randomized controlled trials . Front Pharmacol . 2023;14:1116077. doi:10.3389/fphar.2023.1116077

Panahi Y, Taghizadeh M, Marzony ET, et al. Rosemary oil vs minoxidil 2% for the treatment of androgenetic alopecia: a randomized comparative trial . SKINmed. 2015;13(1):15-21.

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Koyama T, Kobayashi K, Hama T, Murakami K, Ogawa R. Standardized scalp massage results in increased hair thickness by inducing stretching forces to dermal papilla cells in the subcutaneous tissue . Eplasty . 2016;16:e8.

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Hwang SB, Park HJ, Lee BH. Hair-growth-promoting effects of the fish collagen peptide in human dermal papilla cells and C57BL/6 mice modulating Wnt/β-Catenin and BMP signaling pathways . Int J Mol Sci . 2022;23(19):11904. doi:10.3390/ijms231911904

Yagoda MD MR, Gans PhD EH. A nutritional supplement formulated with peptides, lipids, collagen and hyaluronic acid optimizes key aspects of physical appearance in nails, hair and skin . Journal of Nutrition & Food Sciences . 2014;s5. doi:10.4172/2155-9600.s5-002

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By Cristina Mutchler Mutchler is an award-winning journalist specializing in health and wellness content. She is based in Illinois.

MIT Technology Review

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Going bald? Lab-grown hair cells could be on the way

These biotech companies are reprogramming cells to treat baldness, but it’s still early days.

Antonio Regalado archive page

Biologists at several startups are applying the latest advances in genetic engineering to the age-old problem of baldness, creating new hair-forming cells that could restore a person’s ability to grow hair.

Some researchers tell MIT Technology Review they are using the techniques to grow human hair cells in their labs and even on animals. A startup called dNovo sent us a photograph of a mouse sprouting a dense clump of human hair—the result of a transplant of what the company says are human hair stem cells.

The company’s founder is Ernesto Lujan, a Stanford University–trained biologist. He says his company can produce the components of hair follicles by genetically “reprogramming” ordinary cells, like blood or fat cells. More work needs to be done, but Lujan is hopeful that the technology could eventually treat “the underlying cause of hair loss.”

We’re born with all the hair follicles we’ll ever have—but aging, cancer, testosterone, bad genetic luck, even covid-19 can kill the stem cells inside them that make hair. Once these stem cells are gone, so is your hair. Lujan says his company can convert any cell directly into a hair stem cell by changing the patterns of genes active in it.

In biology, we “now understand cells as a ‘state’” rather than a fixed identity, says Lujan. “And we can push cells from one state to another.”

Reprogramming cells

The chance of replacing hair is one corner in a wider exploration of whether reprogramming technology can defeat the symptoms of aging. In August, MIT Technology Review reported on a stealthy company, Altos Labs , that plans to explore whether people can be rejuvenated using reprogramming. Another startup, Conception , is trying to extend fertility by converting blood cells into human eggs.

A key breakthrough came in the early 2000s, when Japanese researchers hit on a simple formula to turn any type of tissue into powerful stem cells, similar to ones in an embryo. Imaginations ran wild. Scientists realized they could potentially manufacture limitless supplies of nearly any type of cell—say, nerves or heart muscle.

In practice, though, the formula for producing specific cell types can prove elusive, and then there’s the problem of getting lab-grown cells back into the body. So far, there have been only a few demonstrations of reprogramming as a way to treat patients. Researchers in Japan tried transplanting retina cells into blind people. Then, last November, a US company, Vertex Pharmaceuticals, said it might have cured a man’s type 1 diabetes after an infusion of programmed beta cells, the kind that respond to insulin.

The concept startups are pursuing is to collect ordinary cells such as skin cells from patients and then convert these into hair-forming cells. In addition to dNovo, a company called Stemson (its name is a portmanteau of “stem cell” and “Samson”) has raised $22.5 million from funders including from the drug company AbbVie. Cofounder and CEO Geoff Hamilton says his company is transplanting reprogrammed cells onto the skin of mice and pigs to test the technology.

Both Hamilton and Lujan think there is a substantial market. About half of men undergo male-pattern baldness, some starting in their 20s. When women lose hair, it’s often a more general thinning, but it’s no less a blow to self-image.

These companies are bringing high-tech biology to an industry known for illusions. There are plenty of bogus claims about both hair-loss remedies and the potential of stem cells. “You’ve got to be aware of scam offerings,” Paul Knoepfler, a stem-cell biologist at UC Davis, wrote in November .

Tricky business

So is stem-cell technology going to cure baldness or become the next false hope? Hamilton, who was invited to give the keynote at this year’s Global Hair Loss Summit , says he tried to emphasize that the company still has plenty of research ahead of it. “We have seen so many [people] come in and say they have a solution. That has happened a lot in hair, and so I have to address that,” he says. “We’re trying to project to the world that we are real scientists and that it's risky to the point I can’t guarantee it’s going to work.”

Right now, there are some approved drugs for hair loss, like Propecia and Rogaine, but they’re of limited use. Another procedure involves cutting strips of skin from someplace where a person still has hair and surgically transplanting those follicles onto a bald spot. Lujan says in the future, hair-forming cells grown in the lab could be added to a person’s head with a similar surgery.

“I think people will go pretty far to get their hair back. But at first it will be a bespoke process and very costly,” says Karl Koehler, a professor at Harvard University.

Hair follicles are surprisingly complicated organs that arise through the molecular crosstalk between several cell types. And Koehler says pictures of mice growing human hair aren't new. “Anytime you see these images,” says Koehler, “there is always a trick, and some drawback to translating it to humans.”

Koehler’s lab makes hair shafts in an entirely different way—by growing organoids. Organoids are small blobs of cells that self-organize in a petri dish. Koehler says he originally was studying deafness cures and wanted to grow the hair-like cells of the inner ear. But his organoids ended up becoming skin instead, complete with hair follicles.

Koehler embraced the accident and now creates spherical skin organoids that grow for about 150 days, until they are around two millimeters across. The tube-like hair follicles are clearly visible; he says they are the equivalent of the downy hair that covers a fetus.

One surprise is that the organoids grow backwards, with the hairs pointing in. “You can see a beautiful architecture, although why they grow inside out is a big question,” says Koehler.

Biotechnology and health

cross section of a head from the side and back with plus symbols scattered over to represent rejuvenated sections. The cast shadow of the head has a clock face.

This researcher wants to replace your brain, little by little

The US government just hired a researcher who thinks we can beat aging with fresh cloned bodies and brain updates.

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Lifestyle changes could counter some of the deterioration.

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How covid conspiracy theories led to an alarming resurgence in AIDS denialism

Widespread distrust of our public health system is reviving long-debunked ideas on HIV and AIDS—and energizing a broad movement that questions the foundations of disease prevention.

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Monday, August 26, 2024

Scalp Exercise for Hair Growth: Boost Your Hair's Natural Strength

Dr. Amy Revene, M.B.B.S., is a general physician at New Hope Medical Center. She graduated from the University of Sharjah in the United Arab Emirates with a Bachelor of Medicine and Bachelor of Surgery (M.B.B.S.) degree. Read more...

Wondering if scalp exercises can actually promote hair growth? You're not alone.

This article explores the science behind this natural method and how incorporating simple daily exercises into your routine might strengthen your hair.

Whether you're dealing with thinning hair or just want to enhance your hair care regimen, scalp exercises could be the key to achieving healthier, fuller locks.

Table of content

What is scalp exercise.

Scalp exercise is a simple, natural technique that involves massaging and moving the muscles on your scalp to improve blood circulation, which may promote hair growth. By gently flexing your scalp muscles or performing a series of massaging motions , you can increase the flow of nutrients and oxygen to your hair follicles.

This natural method supports hair health by stimulating the scalp, making it a great addition to your hair care routine without the need for expensive treatments.

It's an easy, cost-free practice that can be done anytime, helping you maintain stronger, healthier hair over time.

As your leading source for hair health information over the past 4 years, we never compromise on accuracy. When it comes to your health, you deserve information you can truly rely on - and earning your trust is our top priority.

Here's how Scandinavian Biolabs ensures every piece of content meets the highest standards of accuracy and integrity:

Credentialed Experts: Our reviewers are actively practicing doctors and medical researchers
Stringent Reviews: Content undergoes rigorous editing by subject specialists and review by a practicing doctor.
Evidence-Based: We rely on well-established research from trusted scientific sources like peer-reviewed journals and health authorities.
Full Transparency: Our editorial standards, writer credentials, reviewer credentials, correction process, and funding are all publicly documented.
Independent Voice: While we do promote products, we operate in a vacuum to business operations. Our main goal is just an unwavering commitment to providing medically-sound guidance.

You can count on Scandinavian Biolabs to consistently deliver the trustworthy health information you deserve. Read our Editorial Standards .

TrichoAI Hair Loss Analysis

What are the benefits of scalp exercise.

Scalp exercises offer a range of benefits that can contribute to healthier, stronger hair. Taking just a few minutes each day can help improve your scalp's overall health, which can positively impact your hair. Let's dive into some of the key benefits.

1. Improved blood circulation

One of the main benefits of scalp exercises is that they help improve blood circulation to the hair follicles. When you massage or move your scalp, you boost the blood flow, bringing more oxygen and nutrients to the hair roots.

This increased circulation can stimulate hair growth and improve the overall health of your hair, making it stronger and more resilient.

2. Reduced tension and stress

Like other parts of our body, our scalps often carry a lot of tension. Scalp exercises can help release this tension, which feels good and reduces stress-related hair loss.

When your scalp is relaxed, it creates a better environment for hair growth and prevents the tightness that can sometimes lead to thinning hair.

3. Natural scalp detoxification

Regular scalp exercises can also help detoxify your scalp. By stimulating the scalp, you encourage the removal of toxins and buildup that can clog hair follicles.

This natural detox process can help prevent dandruff, itching, and other scalp conditions that might hinder hair growth .

4. Enhanced hair thickness

With consistent scalp exercises, you might notice an improvement in hair thickness . By increasing blood flow and reducing stress, hair follicles are more likely to produce thicker, healthier strands. This can be especially beneficial if you're dealing with thinning hair or hair that has lost its volume.

5. Easy and cost-free hair care

One of the best benefits of scalp exercises is that they are completely free and can be done anytime, anywhere. Unlike expensive salon treatments, scalp exercises require no special products or tools, making them an accessible option for everyone.

Plus, they're easy to incorporate into your daily routine, whether watching TV or getting ready for bed. Incorporating scalp exercises into your hair care routine is a simple yet effective way to support hair growth and maintain a healthy scalp.

Regular practice allows you to enjoy stronger, thicker hair without costly treatments or complicated regimens.

Top scalp exercises for hair growth

Here are some of the top exercises to boost your hair's natural strength and vitality.

1. Scalp massages

Scalp massages are one of the simplest and most effective exercises for hair growth. Using your fingertips, gently massage your scalp in circular motions. This helps increase blood flow to the hair follicles, encouraging hair growth and improving overall scalp health.

You can do this while washing your hair or as a relaxing routine before bed. Adding a few drops of essential oils like rosemary or peppermint can enhance the benefits by nourishing the scalp and soothing any irritation.

2. Forehead pull

The forehead pull exercise involves gently pulling the skin on your forehead upward, stretching the scalp. Place your fingers just above your eyebrows and slowly pull upward, holding for a few seconds before releasing.

This movement helps increase circulation in the front part of your scalp, promoting healthier hair growth.

It's a quick and easy exercise that can be done anywhere, making it a convenient addition to your daily routine.

3. Scalp tapping

Scalp tapping is another effective exercise that can stimulate hair growth. Using your fingertips, gently tap all over your scalp, moving from the front to the back and from side to side.

This technique helps to stimulate blood flow and awaken dormant hair follicles.

It also provides a gentle exfoliation, helping to remove dead skin cells and improve scalp health. Tapping can be done for a few minutes daily, making it a simple yet powerful tool for better hair growth.

4. Neck exercises

Believe it or not, neck exercises benefit your scalp and hair growth. By stretching and moving your neck, you can improve blood circulation to your neck and scalp.

Try gently tilting your head forward, backward, and side to side, holding each position for a few seconds. This increases blood flow to the scalp and can help reduce tension, often contributing to hair loss.

5. Hair tugging

When done gently, hair tugging can stimulate hair growth by increasing blood flow to the scalp. To perform this exercise, take small sections of your hair and gently pull them away from your scalp. Hold for a few seconds before releasing.

This exercise can promote stronger hair, encouraging the roots to stay firmly in place while stimulating circulation. Be careful not to tug too hard to avoid damaging your hair.

Do scalp exercises work?

Scalp exercises can potentially promote hair growth by improving blood circulation to the hair follicles and reducing scalp tension, but their effectiveness may vary from person to person.

While many people report positive results, such as thicker hair or reduced hair loss, it's important to understand that these exercises are not a guaranteed solution for everyone.

How to scalp exercises might help

The main idea behind scalp exercises is to increase blood flow to the scalp, which can help deliver more oxygen and nutrients to the hair follicles. Increased circulation can stimulate the follicles and encourage hair growth.

Additionally, scalp exercises can help reduce stress and tension, which can contribute to hair loss.

Realistic expectations

It's essential to have realistic expectations when trying scalp exercises. While they can be a helpful addition to your hair care routine, they will only produce dramatic results after some time.

Consistency is key, and combining scalp exercises with a healthy diet, proper hair care, and other treatments can offer better results over time.

Complementary approaches

For those experiencing significant hair loss, scalp exercises work best when combined with other treatments, such as topical solutions, dietary supplements, or professional therapies.

Consulting with a dermatologist or hair specialist can also help determine the most effective approach for your situation.

Additional tips for enhancing hair growth

Enhancing hair growth involves more than just scalp exercises. Several additional treatments and lifestyle changes can support healthy, strong hair. Here are five effective methods to consider.

1. Balanced diet rich in nutrients

A well-balanced diet is crucial for healthy hair growth. Eating foods rich in vitamins, minerals, and proteins gives your hair the essential nutrients to grow strong and healthy. Foods like leafy greens, nuts, eggs, and fish are particularly beneficial.

These foods are packed with vitamins such as biotin , vitamin E, and omega-3 fatty acids, all known to support hair health. You can nourish your hair from the inside out by incorporating these into your daily meals.

2. Regular scalp massages with essential oils

Using essential oils during scalp massages can further enhance hair growth. Oils like rosemary, peppermint, and lavender have been shown to stimulate hair follicles and promote growth.

Mix a few drops of your chosen oil with a carrier oil like coconut or jojoba oil and massage it into your scalp.

This boosts circulation and helps nourish the scalp, reduce dandruff, and improve overall hair texture. Regular use can lead to noticeable improvements in hair thickness and shine.

3. Avoiding heat and chemical treatments

Reducing your use of heat styling tools and harsh chemical treatments can prevent hair damage and promote healthier growth. Overusing blow dryers, straighteners, and chemical dyes can weaken the hair shaft, leading to breakage and thinning.

If you must use heat, always apply a heat protectant spray and keep the temperature as low as possible.

Opting for more natural hair care routines and giving your hair time to recover between treatments can significantly improve its strength and resilience.

4. Regular trimming

It may seem counterintuitive, but regular trims are important for healthy hair growth. Trimming the ends of your hair every 6-8 weeks helps prevent split ends, which can travel up the hair shaft and cause further damage.

Keeping your ends healthy encourages stronger growth and prevents unnecessary breakage. Plus, regular trims can help your hair appear thicker and more voluminous.

5. Reducing stress levels

Chronic stress can be a major contributor to hair loss. High stress levels can lead to conditions like telogen effluvium, where hair follicles enter a resting phase, causing hair to fall out.

Incorporating stress-reducing activities such as yoga, meditation, or even daily walks can help maintain hormonal balance and support hair growth.

Taking care of your mental well-being is as important as physical care for promoting healthy hair.

Combining these treatments with consistent scalp exercises can create a comprehensive approach to enhancing hair growth. Each method complements the others, helping you achieve stronger, healthier hair over time.

A better approach for your overall hair health

If you're serious about improving your overall hair health, the Bio-Pilixin® Serum could be a game-changer for you. Experts have crafted this serum to help reduce hair thinning and support new hair growth, making it particularly relevant to anyone with early-stage hair loss.

The Bio-Pilixin® Serum stimulates blood flow and delivers essential nutrients directly to your scalp and hair follicles. This improved circulation is crucial because it helps nourish your hair from the roots, promoting stronger and healthier growth.

The serum is packed with plant growth factors developed through advanced stem cell technology. These factors help nurture your hair follicles, encouraging them to grow stronger and healthier hair. What's great about this formula is that it's inspired by nature.

Many active ingredients are either naturally derived or mimic natural structures, making the serum effective and gentle on your scalp. Plus, it's 100% vegan, so you can feel good about what you're putting on your hair.

Results can vary from person to person, but the numbers are promising. In a clinical trial, 77% of participants noticed reduced hair loss after just 45 days, and 73% saw a measurable increase in hair density after 150 days.

It's a well-rounded product that addresses hair health from multiple angles, making it a potentially valuable addition to your hair care routine for your overall hair health

Bio-Pilixin® Activation Serum | For Women Drug-free & clinically tested Shop Bio-Pilixin® Activation Serum Shop Bio-Pilixin® Activation Serum

Scalp exercises can promote hair growth by improving circulation, reducing stress, and enhancing scalp health. You can significantly support your overall hair health by combining a balanced diet, regular trims, and quality products like Bio-Pilixin® Serum.

The serum's plant-based formula targets hair follicles to reduce thinning and encourage new growth, making it an effective addition to any hair care routine.

If you want to strengthen your hair and combat early-stage hair loss, Bio-Pilixin® Serum could be your solution. Start your journey to healthier hair with Bio-Pilixin® Serum today.

Do scalp exercises help with hair growth?

Yes, scalp exercises can help promote hair growth by improving blood circulation to the hair follicles and reducing scalp tension, which is important for healthy hair growth.

How often should I do scalp exercises to see results?

For best results, it's recommended to do scalp exercises daily or at least several times a week. Consistency is key to noticing improvements in hair growth and scalp health.

Is it possible to grow hair on the scalp?

Hair loss can happen to anyone, but depending on the cause, you may be able to regrow hair naturally. Techniques like scalp massages and using aloe vera or essential oils such as coconut and lemon oil may help.

References:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4740347/
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6380978/
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9710406/
https://www.ncbi.nlm.nih.gov/books/NBK278957/

2024's Global Beauty Sales Are Powered by An Ecommerce & Social Selling Boom

Social selling platforms such as TikTok Shop, Temu, Ebay, Poshmark, Mercari and Shein have collectively captured 6.2% of the total e-commerce market, per NIQ; TikTok leads with 2.6% market share, followed by Temu, with 1.5%.

U.S. prestige beauty sales rose 8% in the first half of 2024, totaling $15.3 billion, while mass beauty remained flat year-over-year, totaling $30.4 billion, per new Circana data. To compare, NIQ puts the growth rate at 5.5% in the same period. Based on its data, "Circana is forecasting growth in prestige beauty for 2024, with continued growth through 2026, albeit at a slower rate," says Larissa Jensen, global beauty industry advisor at Circana. Globally, NIQ data shows that beauty dollar sales grew 10% in all regions, led by Europe and APAC, which were boosted by an expansion of ecommerce and social selling in China and South Korea in particular (more on that below). Here, we break down the latest global and U.S. data points from Circana and NIQ and what they mean for retail and product trends across categories, including fragrance, hair care, skin care and color cosmetics.

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Beauty's Ecommerce & Social Selling Boom

According to NIQ data, online beauty sales grew 14.1% over the last year, helping to drive 8.5% growth in the beauty market, which the firm values at $104.9 billion.

Online sales gains have been particularly strong in China and South Korea, which drove 12.3% growth for APAC. Other ecommerce leaders include Germany and Spain.

For the first half of 2024 alone, 41% of all beauty and personal care sales took place via ecommerce, which NIQ says is evidence of consumers' blended shopping behavior between online and brick-and-mortar.

Free report: What Beauty Brands & Influencers Need to Know about Truth in Marketing

Social selling platforms such as TikTok Shop, Temu, Ebay, Poshmark, Mercari and Shein have collectively captured 6.2% of the total e-commerce market, per NIQ; TikTok leads with 2.6% market share, followed by Temu, with 1.5%.

TikTok charted 50% growth in China, per NIQ, helping drive double-digit sales growth in the market (that said, China's prestige space has been challenged, as seen with Estee Lauder financial results ).

US Beauty Consumers Seek 'Elevated Value' in 2024

In 2024 so far, premium hair care, value-centric fragrances, body skin care, lip makeup and several other categories have propelled growth.

She adds, "Total U.S. consumer spending at retail is flat, but beauty growth continues and prestige beauty specifically continues to be one of the fastest growing industries across the general merchandise and CPG markets."

Jensen concludes, "While consumers may trade down in other areas, within beauty they continue to spend in prestige as the mass market experiences unit sales declines. Interestingly, within the prestige market we see a consumer looking for value though lower-priced brand and product options."

Prestige Fragrance Leads 2024 US Growth

“An accelerated bifurcation is emerging in the beauty industry highlighted by the continued strong growth in prestige in relation to the mass market,” said Larissa Jensen, global beauty industry advisor at Circana.

Top fragrance growth engines included:

Power Sells: Eau de Parfums and Parfums

This is not a new phenomenon. In 2023, Circana reported that higher fragrance concentrations such as eau de parfums and parfums gained three share points . These two product types are leading fragrance growth and rising prices.

Small is Big: Mini Sizes/Travel Sizes

This is also not a new phenomenon. Last year, Circana reported that unit sales for mini women’s fragrances grew at five times the rate of other sizes. For the first half of 2024, units sold for mini scents grew at twice the rate of the fragrance category.

Body Sprays Signal Value-seeking

Body mists and sprays , which feature average prices under $25, more than doubled in sales revenue since the first half of 2023. This trend has continued over the last year-plus, driven by Gen Z .

Gen Z Drives Dupes

Fragrance dupes continue to be a Gen Z favorite . A recent Circana analysis noted that scent dupes offer a similar fragrance experience as a luxury or niche brand, but at a fraction of the cost. These lower cost alternatives are more visible and discoverable than ever, thanks to #PerfumeTok and high Gen Z engagement in the fragrance category.

Gen Z is reportedly "twice as likely to be influenced to purchase a scent that is a dupe or inspired by a more expensive scent," per the Circana analysts, in part because these shoppers believe that lower cost fragrances can be just as good as their more premium counterparts.

In 2024, the dupe culture trend is a "bright spot in the mass fragrance market," with private label brands growing more than 50% year-over-year. Many are marketed as equivalents to luxury and prestige brands.

US Hair Care is Driven by Premiumization in 2024

Hair product sales in the prestige market increased by 10%, based on dollars. Notably, h air products with average prices above $30 grew 3x the rate of lower priced items and now account for 25% of unit sales for the hair care category. That's a 10% gain of market share in just the last three years.

Mass hair care also experienced the largest growth compared to other categories tracked in the Circana report.

Hair care is also the only category with the majority of its sales coming from ecommerce, per Circana. Sales in that channel are experiencing double-digit growth.

Meanwhile, styling and treatments were the fastest-growing areas of the category. In 2023, Circana reported double-digit growth in most hair styling segments .

US Body Care Dominates 2024 Skin Care Sales

Prestige skin care dollar sales increased by 7% in the first half of 2024, leading growth in units sold.

Body skin care is the fastest-growing sector of the overall category, driven by body spray sales, which have grown in the triple digits in the first half of 2024. Double-digit growth has also been seen for body creams, lotions and cleaners.

Per Circana, consumer spending on prestige body products increased by 25% and there are 17% more buyers in this market than there were last year.

Lips & Unique Formats Drive 2024 US Makeup Sales

While prestige makeup remains the largest category in the prestige market, its sales grew 5%, slower than the other categories tracked in the Circana report.

Prestige lip segment sales grew in the double-digits, led by balms and oils. Furthermore, lip gloss and liner were top sales gainers in the mass sector. This lip makeup boom is not a new phenomenon, carrying over from 2023.

Other top performers include unique formats such as:

liquid blushes, sticks and balms
liquid bronzers
stick foundations
stick eye shadows

Innovation Whitespace for 2025 & Beyond

NIQ's report offers a few growth areas brands can pursue for growth in 2025 and beyond. These include:

Products with health & well-being facets paired with aesthetic payoffs
Transparent brands focused on efficacy
Inclusive, customized brands focused on specific skin types and tones, concerns, etc.; these brands may tap AI and other emerging technologies to ensure optimal pairing of consumer and product/regimen
Beauty dupes that deliver performance on par with benchmarks for a lower price

Reawaken the Skin’s Potential!

two women smiling wearing pink lipstick holding lipstick tubes

Oleon Health and Beauty Debuts Radiastar 1436 Natural Guerbet Alcohol for Films, Sensory Effects

On Thursday, September 12, 2024 at 11:00 a.m. Central, Joshua Britton, founder and CEO of Debut, will lead Biotech: How All Brands Can Access the Next Frontier in Beauty.

All Brands Can Access Biotech, the Next Frontier in Beauty

'Gen X is a highly engaged beauty consumer that has grown their spend in beauty at a greater rate than any other generation,' says Circana's Larissa Jensen. 'And in just four short years they will outnumber boomers. The beauty industry needs to start paying closer attention to this cohort.'

Gen X is Beauty's Fastest-growing Spender: Here's How to Engage Them

Neutrogena, which is seeking to engage Gen Z shoppers, has now thrown its hat into the collagen banking ring with the launch of its Collagen Bank range.

Collagen Banking: Beauty’s Long Game

Crown Laboratories x Revance to Merge, Forming Skin Care & Aesthetics Giant

2024’s Fastest-growing Makeup Categories: New Innovation Opportunities

e.l.f. Beauty is reportedly picking up shelf space at Walmart, further driving results for the remainder of the year.

e.l.f. Beauty Targets 25-27% Annual Growth Following Q1 2025 Results

Prequel will soon be available in all Target doors nationwide and Target.com.

Smashbox and Odele Land at Amazon, Curology at Walmart, Prequel at Target: Beauty Retail Rundown

The Calm Restoring Clay Mask for dry, sensitive and irritated skin comprises purple Brazilian clay for skin strengthening, inflammation-fighting punarnava and neem oil, soothing black cumin seed oil and aloe vera, and oat beta glucan to boost skin moisture and reduce redness.

Glorio Brings Single-use Sustainable Beauty to Bloomingdale's

Consumers are testing the limits of beauty innovation like never before, demanding elevated value, efficacy, sustainability and experiences, from product to branding and packaging to marketing and social engagement.

Global Cosmetic Industry Reveals 2025 Beauty Themes

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Advances in Understanding Hair Growth

Bruno a. bernard.

1 L’Oréal Research and Innovation, Asnières-sur-Seine, France

In this short review, I introduce an integrated vision of human hair follicle behavior and describe opposing influences that control hair follicle homeostasis, from morphogenesis to hair cycling. The interdependence and complementary roles of these influences allow us to propose that the hair follicle is a true paradigm of a “Yin Yang” type, that is a cold/slow-hot/fast duality. Moreover, a new promising field is emerging, suggesting that glycans are key elements of hair follicle growth control.

Introduction

The hair follicle is a true paradigm of mesenchymal-epithelial interaction. From early morphogenesis to a fully formed organ, the hair follicle life-cycle is controlled by a dialog between mesenchymal and epithelial compartments 1 . However, this dialog relies on a delicate balance between conflicting and/or opposing influences.

With respect to hair follicle morphogenesis, the reaction-diffusion model explains how slowly diffusing inducers and rapidly diffusing inhibitors orchestrate, through local activation and at distance inhibition, the hair follicle patterned formation. Indeed, the seminal work of A. Turing 2 has been recently confirmed through a formal identification of morphogen activator-inhibitor couples, such as Wnt/DKK1 3 ( Figure 1 ) and EDAR/BMP 4 .

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( A ) Wnt morphogen stimulates its own synthesis as well as that of Dkk1, its inhibitor. Wnt diffuses slowly while Dkk1 diffuses rapidly. ( B ) As a result, in a periodic way, Wnt concentration is higher than that of DKK1, and a hair placode can develop. ( C ) The reaction-diffusion process thus explains the patterned distribution of hair follicles at the surface of the scalp.

Considering its dual mesenchymal and epithelial origin, the hair follicle can be considered a composite organ, with a concentric structure. Dermal and epithelial compartments interact with each other and are characterized by specific differentiation programs. Opposing signaling pathways concur to control the unique behavior of human hair follicle and maintain its unique intrinsic homeostasis. As the activity of diffusible factors, such as growth factors and morphogens, can be modulated by glycans, their possible role in hair growth control must be taken into account.

Hair follicle behavior

The hair follicle is the only organ in mammals that sequentially and repeatedly transits from a phase of active fiber production (anagen) to a resting phase (telogen), through rapid phases of tissue regression (catagen) and regeneration (neogen). A recently published comprehensive guide describes most of the morphological and immunohistological markers that characterize the different stages of the human hair follicle cycle and the intense tissue remodeling events which take place 5 . Of note, hair follicle regeneration relies on the cyclical activation of stem cells 6 . In the human hair follicle, these stem cells are harbored within two distinct reservoirs 7 , 8 , one of them bathing in a hypoxic environment 9 . Instead of a cyclical behavior with an intrinsic automaton, the human hair follicle exhibits a stochastic behavior, the probability of duration of each phase fitting with a lognormal equation 10 . A new concept ( Figure 2 ) postulates the existence of a bi-stable equilibrium 11 which controls human hair follicle dynamics, including an active steady state (the anagen stage) and a resting steady state (the telogen stage), the transition between these two steady states involving either a degradation phase (the catagen phase) or a neo-morphogenesis phase (the neogen phase). It is now believed that mesenchymal and epithelial oscillators control the stochastic autonomous switching between these two steady states 12 , 13 . The transition phases are both controlled by a complex and dynamic network of interacting activators and inhibitors, diffusible morphogens, and growth factors of opposite influences 14 . Of note, however, extrapolating from results only obtained in rodents must be approached with caution, since major differences exist between human and mouse hair follicles in terms of phase duration, synchronicity, tissue remodeling, stem cell reservoirs, and so on.

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An active steady state (ASS) of fiber production (anagen) and a dormant steady state (DSS) (telogen/kenogen) are interspaced by short-lasting phases of regression (catagen) and neomorphogenesis (neogen).

During the active steady state, hair fiber production results from a finely, timely, and spatially tuned choreography of gene expression, which is highly sensitive to stimulatory and inhibitory signals. A number of signaling pathways 15 , cytokines 16 , 17 , neuropeptides 18 , hormones 19 – 22 , prostaglandins 23 , and growth factors 24 are known to modulate the duration of the active steady state of the hair follicle ( Figure 3 ). For example, while insulin-like growth factor (IGF)-1 is required for anagen maintenance 25 , 26 , fibroblast growth factor (FGF)-5 appears to be a crucial regulator of hair length in humans 27 , as a strong inducer of the catagen phase. Moreover, the human hair follicle is endowed with an autonomous androgen metabolism 28 , a strict dependence on arginine 29 , polyamines 30 , and glucose 31 for growth, and a specific immunological response 32 . The hair follicle is also endowed with a full prostaglandin metabolism and a complex network of prostaglandin (PG) receptors 33 , 34 . Recent data suggest that a delicate equilibrium between PGE2/PGF2a on the one hand and PGD2 on the other hand controls the duration of the active steady state. PGE2/PGF2a promotes hair growth maintenance, while PGD2 inhibits it and triggers anagen to catagen transition 35 . Finally, re-evaluating the mechanisms by which agents such as cyclosporine A 36 or JAK-STAT inhibitors 37 promote human hair growth might help to identify new key genes and pathways involved in the control of hair growth.

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Summary of diffusible factors having positive (Yang) or negative (Yin) effects on hair growth and cycling.

Besides the active steady state, new data demonstrate that the resting steady state is not as quiescent as suspected and can be divided into a refractory period and a permissive period. Indeed, during the telogen phase, the follicle is under the influence of factors that would repress the onset of the neogen phase and factors that would trigger it. Specifically, a strong expression of bone morphogenetic protein (BMP) and FGF-18 defines the refractory period, during which the neogen onset is prevented. The progressive increase in the production of BMP antagonist noggin, Wnt/Fzz/b-catenin pathway activators, and transforming growth factor (TGF)-β2 then reaches a critical threshold that shifts the telogen follicle to a competency status, receptive to FGF-7, secreted by the nearby dermal papilla, and, ultimately, triggers the onset of the neogen phase 38 .

Glyco-biology of the human hair follicle

It is clear from the above that the complex and rhythmic behavior of the human hair follicle is under the control of multiple, intricate pathways with opposing influences. In this respect, the interdependence and complementary roles of these influences allow us to propose that the hair follicle is a true paradigm of a “Yin Yang” type duality and harmony. However, in our opinion, the fine tuning of these influences cannot solely rely on the timely and spatially controlled gene expression, but also on glycans, “the third revolution in evolution” 39 . Glycans are endowed with such a huge molecular diversity that they can be considered the third language of life, after DNA and proteins.

Linear or branched oligosaccharides can be attached to a protein backbone via O-(serine/threonine) or N-(asparagine) linkages. They form the large class of N-Complex type glycans. Glycosaminoglycans are linear copolymers of 6-O-sulfated disaccharide units which define them as chondroitin, dermatan, keratin, or heparin sulfates. Proteoglycans have one or more glycosaminoglycan side chains attached to a core protein. Glycosaminoglycans, proteoglycans, and glycan moieties of glycoproteins have long been known to play important roles in the maintenance of protein conformation and solubility, protection against proteolytic degradation, mediation of biological activity, intracellular sorting and externalization, and embryonic development and differentiation 40 – 45 . The distribution of proteoglycans in the human hair follicle was originally described in the early 1990s, namely for chondroitin sulfate, dermatan sulfate, and heparin sulfate proteoglycans 46 , for syndecan 1, perlecan and decorin 47 , and for versican 48 . Thanks to the availability of new immunological tools, the distribution of proteoglycans in the human hair follicle has been further refined 49 ( Figure 4 ), highlighting a complex, dynamic, and regionalized network of proteoglycans. With respect to cell surface complex type N-glycans, the use of specific fluorescently labeled lectins (saccharide-binding proteins) revealed a differential N-glycan composition among the different hair follicle compartments 50 – 52 ( Figure 5 ).

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Diagram shows the distribution of versican, perlecan, syndecan 1, aggrecan, biglycan, and heparan sulfate proteoglycans in the different hair follicle compartments. BM, basement membrane; CTS, connective tissue sheath; IRS, inner root sheath; ORS, outer root sheath.

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Distribution of N-glycans identified by their reactivity with fluorescently labelled Pisum sativum agglutinin (PSA), wheat germ agglutinin (WGA) and Ulex europeus agglutinin (UEA) in both skin and hair follicles. PSA mainly decorates the dermal compartments of skin and hair follicles, while WGA decorates both dermal and epithelial compartments. UEA only decorates the epidermis stratum granulosum and the hair follicle IRS.

What could be the role of these glycans? It has been known for quite a long time that growth factor activation could be regulated by proteoglycans 53 , 54 and that heparan sulfate proteoglycans were involved in fine-tuning mammalian physiology 55 and in cell signaling during development 56 . With respect to key regulators of hair follicle growth and cycling, syndecans modulate Wnt signaling cascades 57 , the glycosaminoglycan chains of proteoglycans shape Hedgehog gradients and signal transduction 58 , and O-linked glycosylation controls Notch1 interaction with its cognate Delta-like 4 receptor 59 . Decorin, a small leucine-rich proteoglycan, directly modulates TGF-β, epidermal growth factor (EGF), IGF-1 and hepatocyte growth factor (HGF) signaling, all known actors of hair follicle cycling 60 , and appears to act as an anagen inducer 61 . Altogether, these recent results designate glycans as long time ignored key players in hair growth control. But, on top of that, enzymes can further modulate the biological activity of these glycans. For example, fucosyl transferase is absolutely required for Notch activity, and disruption of fucosyl transferase expression in murine hair follicle lineages results in aberrant telogen morphology, a decrease of bulge stem cell markers, a delay in anagen re-entry, and dysregulation of proliferation and apoptosis during the hair cycle transition 62 . With respect to proteoglycans, heparanase (an endoglycosidase that cleaves heparin sulfate) was found expressed in the outer root sheath of murine hair follicles and identified as an important regulator of hair growth through its ability to release heparin-bound growth factors 63 . In the human hair follicle, however, heparanase was found located in the inner root sheath. Its inhibition provoked an immediate transition from anagen to catagen 64 . In this case, the HPSG/heparanase network appears to be a key controller of internal hair follicle homeostasis.

Finally, extracellular sulfatases appear to be critical regulators of heparin sulfate activities. Sulf1 and Sulf2, by removing glucosamine-6S groups from specific regions of heparan sulfate chain, modulate (a) Wnt interaction with its cognate receptor Frizzled, (b) BMP signaling by releasing BMP antagonist Noggin, and (c) FGF-2 ability to form the functional FGF-2-HS-FGFR ternary complex 65 , 66 . Of note, TGF-β1, by inducing Sulf1 expression 67 , might indirectly modulate Wnt, BMP, and FGF-2 activities, which could explain its inhibitory effect on hair growth. From a clinical point of view, alterations of glycosaminoglycan degradation provoke mucopolysaccharidoses and abnormalities in hair morphology 68 , which can be reversed by appropriate enzyme replacement therapy 69 .

The hair follicle is clearly endowed with a unique behavior. Its bi-stability and the intense remodeling processes that it provokes rely on the permanent dialog between opposing and complementary influences, impacting all follicle compartments. From this interdependent duality, one can easily understand that an optimal way to describe the complex equilibrium which controls hair follicle homeostasis is the concept of “Yin Yang”. Until recently, the understanding of hair growth mainly relied on deciphering the patterns of gene expression within the different hair follicle compartments throughout the hair cycle 70 , 71 . From now on, the fine-tuning of the activities of growth factors and morphogens by the modulating effects of glycans will also have to be taken into consideration.

From a prospective point of view, it is likely that a better understanding of hair diseases, and more specifically the role of inflammation and immune response in the development of alopecia areata 72 and androgenetic alopecia 73 , will likely provide further insights into the role of the so-called immune privilege 74 in hair growth control. Moreover, with the advent of mature metabolomics technologies 75 coupled with in vitro human hair growth technology 76 , one can predict that this integrative approach will permit us to identify these key metabolic pathways sustaining normal hair growth.

Acknowledgements

I thank Ms E. Debecker (L’Oréal R&I) for her expert assistance in lectin labeling experiments.

[version 1; referees: 2 approved]

Funding Statement

The author(s) declared that no grants were involved in supporting this work.

Editorial Note on the Review Process

F1000 Faculty Reviews are commissioned from members of the prestigious F1000 Faculty and are edited as a service to readers. In order to make these reviews as comprehensive and accessible as possible, the referees provide input before publication and only the final, revised version is published. The referees who approved the final version are listed with their names and affiliations but without their reports on earlier versions (any comments will already have been addressed in the published version).

The referees who approved this article are:

Rodney Sinclair , Epworth Dermatology, Victoria, Australia No competing interests were disclosed.
Gill Westgate , Centre for Skin Sciences, University of Bradford, Bradford, BD7 1DP, UK No competing interests were disclosed.

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Wilmington, Delaware, United States, Transparency Market Research Inc. -, Aug. 26, 2024 (GLOBE NEWSWIRE) -- The global hair wax stick market (헤어 왁스 스틱 시장) was projected to attain ...
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U.S. prestige beauty sales rose 8% in the first half of 2024, totaling $15.3 billion, while mass beauty remained flat year-over-year, totaling $30.4 billion, per new Circana data. To compare, NIQ puts the growth rate at 5.5% in the same period. Based on its data, "Circana is forecasting growth in prestige beauty for 2024, with continued growth through 2026, albeit at a slower rate," says ...
Advances in Understanding Hair Growth
Introduction. The hair follicle is a true paradigm of mesenchymal-epithelial interaction. From early morphogenesis to a fully formed organ, the hair follicle life-cycle is controlled by a dialog between mesenchymal and epithelial compartments 1. However, this dialog relies on a delicate balance between conflicting and/or opposing influences.

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