Article Information

Rene Antonio Rivero-Jimenez^1,2*, Muhammad Touseef Haider¹, Ubaid Rahman Moorakkan¹, Yendy Ventura-Carmenate^1,2,3, Antonio Alfonso Bencomo-Hernandez¹

¹Abu Dhabi Stem Cells Center, Stem Cells Laboratory, Abu Dhabi, United Arab Emirates.

²United Arab Emirates University. Office of Research and Graduated Studies, College of Medicine and Health Science, Abu Dhabi, United Arab Emirates.

³Yas Clinic Khalifa City Hospital, Abu Dhabi, United Arab Emirates

*Corresponding Author: Rene Antonio Rivero-Jimenez, Abu Dhabi Stem Cells Center, Stem Cells Laboratory, Abu Dhabi, United Arab Emirates.

Received: 26 February 2024; Accepted: 07 March 2024; Published: 28 March 2024

Citation: Rene Antonio Rivero-Jimenez, Muhammad Touseef Haider, Ubaid Rahman Moorakkan, Yendy Ventura-Carmenate, Antonio Alfonso Bencomo-Hernandez. Mechanisms Involved in Human Hair Growths Relevant for Regenerative Medicine Therapies. Archives of Clinical and Biomedical Research. 8 (2024): 121 -128.

Abstract

Keywords

Hair growth; Follicle; Regeneration; Wnt; β-Catenin; Stem cells; Perivascular niche; Alopecia

Article Details

Abbreviations:

AGA: Androgenic alopecia; ALP: Alkaline phosphatase; APM: Arrector pili muscle; bFGF: Basic fibroblast growth factor; BIO: (2′Z,3′E) Bromoindirubin 3′oxime; BMP: Bone morphogenetic protein; CK15: Cytokeratin 15; CK19: Cytokeratin 19; Dkks: Dickkopfs; DP: Dermal papilla; DPSCs: Dermal papilla stem cells; Eda-A1: Ectodysplasin; EGF: Epidermal growth factor; FGF: Fibroblast growth factor; GSK3: Glycogen synthase kinase 3; HF: Hair follicle; HFSCs: Hair follicle stem cells; HGF: Hepatocyte growth factor; HSC: Hair stem cells; IGF1: Insulin-like growth factor 1; IGFBP1: Insulin-like growth factor binding protein 1; IL6: Interleukin 6; MCSF: Macrophage colony-stimulating factor; MCSFR: Macrophage colony-stimulating factor receptor; MSCs: Mesenchymal stem cells; ORS: Outer root sheath; PDGF: Platelet-derived growth factor; PDGFRα: Platelet-derived growth factor receptor alfa; PDGFRβ: Platelet-derived growth factor receptor beta; PGD2: Prostaglandin D2; PGE2: Prostaglandin E2; SCs: Stem Cells; Shh: Sonic hedgehog; α-SMA: α-smooth muscle actin; TGFβ1: Transforming growth factor beta1; TNF: Tumor necrosis factor; VEGF: Vascular endothelial growth factor; WIHN: Wound-induced hair neogenesis; Wnt3a: Wingless-type MMTV integration site family, member 3A

Introduction

Hair is a defining feature of mammals and has critical functions, including skin protection, production of sebum, apocrine sweat and pheromones, social and sexual interactions, thermoregulation, and provision of stem cells (SC) for skin homeostasis, regeneration, and repair [1]. Unwanted hair loss can pose psychosocial distress to affected individuals, particularly women [2]. Hair regeneration depends on activating hair follicle SC (HFSCs) [3-5]. The hair follicle (HF) is considered a “mini organ,” consisting of intricate and well-organized structures originating from the HF stem and progenitor cells [1]. Dermal papilla (DP) cells are the main components of the mesenchymal compartments in the hair bulb. They are instrumental in generating signals to regulate the behavior of neighboring epithelial cells during the hair cycle. Mesenchymal-epithelial interactions within the DP niche derive HF embryonic development and the postnatal hair growth and regeneration cycle [1]. Human and murine HFs share the same principal cell types and the same essential features of organization and function. While hair research in the mouse has long been the foundation of our understanding of hair biology, [6] recent work has provided insight into human HF biology, facilitating the development of novel therapies for skin disorders [7]. The HFSCs and the DP stem cells (DPSCs) interact in the hair’s growth and guarantee appropriate hair recovery and regeneration conditions [8]. Nevertheless, despite the DPSCs being harmed, in the case of androgenic alopecia (AGA) patients, HFSCs are saved in patchy, for which this kind of hair loss can be reversible [8]. Due to the importance of this knowledge for hair loss therapy using SC from the HF in humans, we decided to do this bibliographic review to help develop regenerative medicine in Abu Dhabi.

Method

To compile this review, we conducted a comprehensive search of the Google Scholar and PubMed databases for relevant references from 2000 to 2024 using the following terms: “alopecia”, “hair growth”, “hair follicules stem cells”, “dermal papilla”, “stem cells therapy”, and “cellular factor.” To describe detectable cell therapies available and different possibilities for improvement, we based our review on analyses conducted by various authors. Our literature review primarily focused on the embryological development of human hair, human hair follicles, stem cells, stem cell factors and stem cells use in hair follicle regeneration. Also, the cited bibliography of each selected paper was revised to identify any further relevant publications that aligned with our search objectives. The full text of each article included in this review was examined. Finally, we selected only the articles written in English.

Embryological Development of Human Hair

Human HF develops in embryonic life in four distinct stages, beginning in the ninth week of intrauterine life [7]. The HF structure is preserved across multiple tissue types, including the nails, teeth, and most exocrine glands, [9] and reciprocal interactions between the epidermal placode and the underlying dermal cells crucially determine HF formation [10]. The coordinated interaction of the various cells that make up the body is key to multicellularity. Indeed, patterning embryos, establishing cell type diversity, and forming tissues and organs rely on cell-to-cell communication during development [11]. Thus, arguably, one of the most important principles of developmental biology involves “one group of cells changing the behavior of an adjacent set of cells, causing them to change their shape, mitotic rate, or fate.” An array of signaling pathways is thought to mediate this communication. Although many of the key pathways have not yet been identified, it is understood that Wnt, Sonic hedgehog (Shh), transforming growth factor-β/bone morphogenic protein (TGF-β/BMP), fibroblast growth factor (FGF), and the various tumor necrosis factor (TNF) paracrine signaling factors have fundamental roles [12]. The mesenchyme initiates signaling, stimulating the thickening of the epidermis and the formation of a hair placode [13]. Once established, the placode cells induce the mesenchymal cells to form a dermal condensate that ultimately forms the HF dermal papilla [14]. Signals from the dermal condensate then promote the epithelial cells’ ingrowth into the dermis [13]. Further reciprocal epithelial-mesenchymal signaling likely induces maturation and formation of the different HF lineages. These processes have been classically categorized into three phases: induction, organogenesis, and cytodifferentiation [15]. The surrounding dermal cells conjugate around the placode and form a hair bud. The hair bud proliferates, lengthens, and invaginates into the dermis, creating the hair peg. Mesenchymal tissue then accumulates in the area, resulting in the hair bulb. Differentiation of the surrounding epithelial cells results in the formation of the HF wall, hair epithelial sheath, and a small swelling that will eventually form the sebaceous gland. Proliferation and keratinization of central epithelial cells form the hair cone. The HF is complete after the sebaceous gland differentiation and when the hair protrudes through the skin. HFs throughout the body develop at different rates, but by 21 weeks of fetal life, all areas have at least one HF. The development of HF progresses in a cephalocaudal direction, and by the time there are long hairs on the face and scalp, many areas of the trunk and extremities have hairs within the cellular sheaths or hairs partially protruding through the epidermis [16]. Local gradients of HF activators and inhibitors govern the mechanisms determining HF fate [17]. Wnt, ectodysplasin-A1 (Eda-A1), and noggin induce placode formation [18]. Signals that inhibit HF development remain yet to be determined. Wnt activity within and around developing hair placodes is under tight control, which is important given its integral role in HF cycling [18] and the potential for skin tumor formation with overactive epidermal Wnt/β-catenin signaling [19]. As in the “Turing model of reaction-diffusion systems,” previously described in feather development, extracelular secreted Wnt and Dickkopfs (Dkks) likely direct placode formation through a reaction-diffusion system. Small-molecular-weight Wnt inhibitor Dkk4, for example, easily diffuses and inhibits Wnt signaling in the interfollicular epidermis, whereas larger Wnt molecules remain within the placode [20].

Human hair follicular stem cells

Human HFSCs (hHFSCs) are less known than murine HFSCs (mHFSCs). A variety of molecules are involved in the networks that critically regulate the fate of hHFSCs, such as factors in HF growth and development -in the Wnt, Shh, Notch, and BMP pathways, and that suppress apoptotic cues (the apoptosis pathway)-It appears that specific markers are normal in both human and mouse HFSCs: CD34, [21, 22] Cytokeratin 15 (CK15), [7, 21], Ctrokeratin 19 (CK19), [21, 23], and CD200. [21, 22] T he presence of different markers (i.e., Sox9 and LHX2) requires further examination. [24] Markers found in hHFSCs are PHLDA1 and EpCAM/Ber-EP4, valuable markers of the telogen-optional hair germ [21]. Although PHLDA-1 is not specifically expressed in hHFSCs, it can also be expressed in sweat glands and epidermal melanocytes [25]. DP cells present distinctive markers, including the cells from HF, dermal fibroblasts, and alkaline phosphatase (ALP) that is critical for both human and murine HFs, and it is the most explicit of the markers, wherein its high action is considered a marker of DP cells separation [26]. Additionally, α-smooth muscle actin(α-SMA), laminin, fibronectin, and CD133 expression have been observed in DP cells [26]. Marker expressions are modified in disease states. For instance, the immunoreactivity of CK15 is diminished in individuals with patchy alopecia. It is also identified in AGA [27]. HF of the scalp’s front part displays a reduced CD34 in AGA, whereas its appearance is conserved in HF of the occipital locale [28]. In patchy alopecia, CD200, another marker of matrix cells, is expressed ineffectively, which might indicate a low immune benefit contributing to pathogenesis (i.e., the response of auto-reactive lymphocytes) [27]. Hair stem cells (HSCs) in the bulge remain resting for most of their lives, yet they can be actuated by relying upon the hair circle stage. The interpretation of the hair circle in humans has a few constraints due to the distinctive lengths of anagen, asynchrony of the human cycle, or the alternate response to the impact of hormonal variables [29]. Different papers reported the results of human scalp skin xenografted onto immune-compromised mice to set up the hair circle course in vivo in people [29].

Table 1: The main phases of hair growth.

The action of SCs in the bulge is controlled by its microenvironment (i.e., a supposed niche). This microenvironment incorporates the daughter cells of the SCs in the bulge, which enact their self-recovery ahead of schedule and in the late anagen stages [31]. SCs are fundamentally influenced by the DP’s mesenchymal stem cells (MSCs), which are in close contact with the germinal matrix cells isolated by the basal membrane [32]. They appear to be of vital significance in the activation of hair growth and signal transmission during recovery [33]. Investigations have demonstrated that hair recovery is impossible after laser treatment because the HF cycle stops at the telogen stage without advancing to the anagen stage [32].Infusions of exosomes obtained from DP cells to HFs have been found to accelerate the passage of anagen and catagen delay employing the β-catenin and SHH pathways. [34] HFSCs are additionally influenced by fibroblasts in the reticular and papillary layers of the dermis, in addition to the subcutaneous tissue [32]. Inside the niche, melanocyte SCs oversee the formation of mature melanocytes that confer color to maturing hair. The survival and growth of MSCs relies on signs transmitted by the HF epithelial cells (HFECs), for instance, the TGF-β or the Wnt pathway [32]. The extracellular matrix is another part of the microenvironment. It explicitly influences the SCs through the arrangement of the basal layer, in which undifferentiated cells are in contact and regulated, for instance, by integrins [33]. Adult neural, mesenchymal, and hematopoietic SCs neighbor the vasculature, supplying oxygen and nutrients and providing molecular signals to the SCs [6,35,36], mainly through endothelial cells [37]. Intimate molecular communication from the vascular niche to the SCs contributes to tissue homeostasis and repair. Reverse signaling, from SCs to the neighboring niche, was also shown in zebrafish, where hematopoietic SCs can remodel the perivascular niche [38]. Little is known about skin vasculature cross-talking with adult HFSCs. HFSCs reside in the upper segment of the HF, known as the bulge, and are embedded deep into the skin dermis. During the hair circle, bulge HFSCs periodically regenerate the temporary lower HF region (bulb), which grows downward into the hypodermis [39]. HFs undergo morphologically recognizable and synchronous phases of remodeling, known as anagen (Bulb growth), catagen (bulb destruction), and telogen (quiescence and rest) [37].

At catagen, a subset of quiescent HFSCs leave the bulge and form the secondary hair germ, which replaces the apoptotic hair bulb. The skin loses most of its fat in the hypodermis, shrinks considerably in thickness, and the HFs enter the resting phase or telogen. In anagen, signals from the environment, including the fat progenitors [40], activate the quiescent HFSCs in the hair germ to produce a new hair bulb with a newly growing hair shaft [39] The bulge HFSCsthatgo into the hair germ are subsequently replenished at anagen by self-renewing symmetric divisions of the bulge SCs [41,42] The fat layer in the hypodermis and surrounding the growing hair bulb also regenerates in parallel with the HF at anagen [40]. Although poorly understood, the skin vasculature is remodeled along with the massive changes in the skin structure and thickness that result in the destruction and reconstruction of the highly vascularized hypodermis. In human skin, vasculature-associated cells known as pericytes may promote stem cell proliferation of the inter-follicular epidermis [43], although any effects on HFSC activation have not been addressed. Furthermore, a permanent vascular structure, known as the upper venule annulus, neighbors the upper hair bulge region at all hair circle stages [44], but the significance of this association is not understood. Importantly, angiogenesis and recruitment of blood vessels promote more robust hair shaft production, presumably by providing nutrients to rapidly dividing hair matrix progenitor cells in the bulb during full anagen [45,46]. However, these studies have not examined the potential cross-talk of vasculature with quiescent HFSC at earlier hair circle stages (catagen/telogen). Hormones such as androgens are an essential regulator for hair growth, and they have paradoxical effects on HFs in different body regions. It is known that vellus hair refers to our body’s thin,tinyhairs. We can find them if we look closely at seemingly hairless areas, such as our ear lobes or faces. Androgens can stimulate the transformation of small vellus HFs in some regions of our body into large terminal HFs after puberty, such as the beard, pubic hair, and axillary hair [47,48]. On the contrary, in the scalp, genetically predisposed individuals of androgenic alopecia or male pattern baldness, androgens inhibit hair growth, leading to progressive HF miniaturization. [49] Hyperandrogenism in females can lead to hirsutism with excessive male pattern hair growth. [50] These paradoxical effects of androgens on human hair growth have long been a puzzle [51,52]. Androgens act through the intracellular androgen receptor. In HFs, androgen receptors are mainly expressed by DP [53,54] In contrast, keratinocytes do not express androgen receptors or show androgen receptor-dependent signaling activation, suggesting that keratinocytes may not be the primary responding cells in HFs [55,56]. It is already demonstrated that Piloerection (goosebumps) requires concerted actions of the HF, the arrector pili muscle (APM), and the sympathetic nerve, providing a model to study interactions across epithelium, mesenchyme, and nerves. It was shown that APMs and sympathetic nerves form a dual-component niche to modulate HFSC activity. Sympathetic nerves form synapse-like structures with HFSCs and regulate HFSCs through norepinephrine, whereas APMs maintain sympathetic innervation to HFSCs. Without norepinephrine signaling, HFSCs enter deep quiescence by downregulating the cell cycle and metabolism while upregulating quiescence regulators Foxp1 and Fgf18. During development, HFSC progeny secretes Shh signals to direct the formation of this APM-sympathetic nerve niche, which controls adult HF regeneration. Those results reveal a reciprocal interdependence between a regenerative tissue and its niche at different stages. They demonstrate that sympathetic nerves can modulate SCs through synapse-like connections and neurotransmitters to couple tissue production with demands [57]. Some SC factors and small molecules promote hair growth by different mechanisms (See Table 2).

Table 2: Stem cell factors and small molecules that promote hair growth and their mechanisms of action Ref [58].

Legend: bFGF: basic fibroblast growth factor; BIO: (2′Z,3′E) Bromoindirubin 3′oxime; BMP: bone morphogenetic protein; DP: dermal papilla cells; EGF: epidermal growth factor; GSK3, glycogen synthase kinase 3; HGF: hepatocyte growth factor; IGF1: insulin-like growth factor 1; IGFBP1: insulin-like growth factor binding protein 1; IL6: interleukin 6; MCSF: macrophage colony-stimulating factor; MCSFR: macrophage colony-stimulating factor receptor; ORS: outer root sheath; PDGF: platelet-derived growth factor; PDGFRα: platelet-derived growth factor receptor alpha; PDGFRβ: platelet-derived growth factor receptor beta; PGD2: prostaglandin D2; PGE2: prostaglandin E2; TGFβ1: transforming growth factor β1; VEGF: vascular endothelial growth factor; WIHN: wound induced hair neogenesis; Wnt3a: wingless-type MMTV integration site family, member 3A.

Stem Cell Use in Hair Follicle Regeneration

HF are immunologically privileged places, like the brain, eyes, and testicles, under the influence of the neuroendocrine-immune network [59].

In physiological conditions, this is characterized by:

• Low expression or absence of the main MHC I antigens,
• The presence of malfunctioning Langerhans cells,
• Local expression of immunosuppressive substances (TGF-β1 and α-melanocytes MSH) [59].

Owing to this, they can be easily used in transplantation. Multipotent SCs can regenerate HF with sebaceous glands in the skin. In the current state of knowledge, SCs can be used to regenerate hair in several therapeutic strategies:

• Reversing the pathological mechanisms that contribute to hair loss (especially in AGA)
• Regeneration of complete HF from their parts (cells in the bulge can regenerate a whole hair)
• Neogenesis of HF from a stem cell culture with isolated cells or tissue engineering [60,61].

The presence ofSCsin somatic tissues has been well establishedusingfunctional tissue cell transplantation assays. [62] However, their isolation and propagation have proven difficult.

Methods to isolate and expandSCsfrom somatic tissue, particularly without significant differentiation, are highly desirable. Some questions have been raised regarding how multipotent adultSCsrelate to embryonicSCs. Thus, obtaining and cultivating many types of somaticSC is essential. In particular, the availability of a method for producingHFSCs and melanocyteSCsfrom adult tissues would significantly contribute to cell replacement therapies and tissue engineering. For example,HFSCscan producehair, sweat glands, sebaceous glands, and skincells [63].One of the problems encountered with artificial skin is that it does not have sweat glands or sebaceous glands, leading to problems with thermo-regulation and dryness, respectively, when large segments are grafted. It would be desirable to have othercellsthat could be used in tissue engineering applications, such as generating functional skin grafts. There has been considerable difficulty in obtaining human somaticHFSCsthat can be propagated and cultured ex vivo. One factor is the predominant way somaticSCsdivide is by asymmetric cell kinetics. During asymmetric kinetics, one daughter cell divides with the same kinetics as itsstem cell parent, while the second daughter gives rise to a differentiating non-dividing cell lineage. The second daughter may differentiate immediately, or, depending on the tissue, it may undergo a finite number of successive symmetric divisions to give rise to a larger pool of differentiatingcells.

Such asymmetric cell kinetics significantly hinder cell expansion in vitro. [64-66] Inculture, continued asymmetric cell kinetics results in dilution andlossof an initial relatively fixed number ofSCsby accumulating much greater numbers of their terminally differentiating progeny. If a sample includes exponentially growingcellsand somaticSCs, their growthwill rapidly overwhelm the somaticSCs, leading to their dilution. Even in instances where it is possible to select for relatively purer populations, for example, by cell sorting, asymmetric cell kinetics prevent expansion. Another factor is that during thehairgrowth cycle, thecellsare believed to migrate from the bulge region to a place at the base of the HF known as the bulb [67]. These migratory patterns and the general difficulty of dissecting these regions from HFhave foiled attempts to establish HFSC lines.

Conclusions

SCs are being investigated in applications in male pattern baldness and other forms of alopecia of the human scalp. Stem cells are being studied to see if the hair can be replenished using patients’ MSCs from the base of the existing follicles, fat cells, and bone marrow SCs or embryonic umbilical SCs to stimulate hair growth or replacement. Other modalities, such as SC-derived nutrient medium and SC-derived exosomes, are novel approaches to future hair loss therapy [68]. Recent studies revealed that SCs may be directly injected into the scalp to allow the growth of new HF in males or females and correct alopecia. SCs may also be used in growth factor stimulation of existing inactive and atrophic follicles to become viable and active follicles yet again [68]. Additional studies indicate that various regulatory mechanisms may be utilized to reinitiate the existing inactive follicle cells to regrow hair in male pattern baldness. SCs injected into the scalp could aid these regulatory mechanisms. Nevertheless, we have developed a simple, reliable, and safe method in our laboratory to isolate suchSCsfrom an individual and expand them as primary culture ex vivo for hair loss therapy without establishing a cell line but only for autologous use.

Author contributions

All authors contribute to this review. RARJ and AABH conceived and designed the study. RARJ wrote the manuscript. RARJ, MTH, URM, YVC, and AABH reviewed and edited the manuscript. All authors contributed to the article and approved the submitted version.

Funding

This publication was supported by the Abu Dhabi Stem Cells Center (ADSCC) because all authors are staff members of the research center. The content of this critical review is solely the authors' responsibility and does not necessarily represent the official views of the ADSCC.

Data availability

Not applicable; all information is gathered from published articles.

Code Availability

Not applicable

Declarations

The authors report no proprietary or commercial interest in any product mentioned or concept discussed in this article.

Ethical approval

Not applicable

Consent to participate

Concept for publication

Not applicable

Conflict of interest

The authors declare that the research was conducted without any commercial or financial relationships that could be construed as a potential conflict of interest.

References

1. KS Houschyar, MR Borrelli, C Tapking, et al. Molecular Mechanisms of Hair Growth and Regeneration: Current Understanding and Novel Paradigms. Dermatology 236 (2020): 271-280.
2. EL McGarvey, LD Baum, RC Pinkerton, et al. Psychological Sequelae and Alopecia Among Women with Cancer. Cancer Pract 9 (2001): 283-289.
3. G Cotsarelis, TT Sun, RM Lavker. Label-retaining cells reside in the bulge area of pilosebaceous unit: Implications for follicular stem cells, hair cycle, and skin carcinogenesis. Cell 61 (1990): 1329-1337.
4. V Greco, T Chen, M Rendl, et al. A Two-Step Mechanism for Stem Cell Activation during Hair Regeneration. Cell Stem Cell 4 (2009): 155-169.
5. YC Hsu, HA Pasolli, E Fuchs. Dynamics between Stem Cells, Niche, and Progeny in the Hair Follicle. Cell 144 (2011): 92-105.
6. M Oh, JE Nör. The Perivascular Niche and Self-Renewal of Stem Cells. Front Physiol 6 (2015).
7. M Ohyama, A Terunuma, CL Tock, et al. Characterization and isolation of stem cell-enriched human hair follicle bulge cells. J Clin Invest 1 (2006): 249-260.
8. P Mohammadi, KK Youssef, S Abbasalizadeh, et al. Human hair reconstruction: close, but yet so far. Stem Cells Dev 25 (2016): 1767-1779.
9. MR Schneider, R Schmidt-Ullrich, R Paus. The Hair Follicle as a Dynamic Miniorgan. Current Biology 19 (2009): R132-R142.
10. CC Yang, G Cotsarelis. Review of hair follicle dermal cells. J Dermatol Sci 57 (2010): 2-11.
11. F Sotomayor-Lugo, N Iglesias-Barrameda, Y Castillo-Aleman, et al. The Dynamics of Histone Modifications during Mammalian Zygotic Genome Activation. Int J Mol Sci 25 (2024): 1459.
12. N Perrimon, C Pitsouli, BZ Shilo. Signaling Mechanisms Controlling Cell Fate and Embryonic Patterning. Cold Spring Harb Perspect Biol 4 (2012): a005975-a005975.
13. MH Hardy. The secret life of the hair follicle. Trends in Genetics 8 (1992): 55-61.
14. WM Woo, HH Zhen, AE Oro. Shh maintains dermal papilla identity and hair morphogenesis via a Noggin-Shh regulatory loop. Genes Dev 26 (2012): 1235-1246.
15. P Rishikaysh, K Dev, D Diaz, et al. Signaling Involved in Hair Follicle Morphogenesis and Development. Int J Mol Sci 15 (2014): 1647-1670.
16. KA Holbrook, GF Odland. Structure of the Human Fetal Hair Canal and Initial Hair Eruption. Journal of Investigative Dermatology 71 (1978): 385-390.
17. C Li, A Pearson, C McMahon. Morphogenetic Mechanisms in the Cyclic Regeneration of Hair Follicles and Deer Antlers from Stem Cells. Biomed Res Int 2013 (2013): 1-21.
18. J Stark, T Andl, SE Millar. Hairy Math: Insights into Hair-Follicle Spacing and Orientation. Cell 128 (2007): 17-20.
19. A Blagodatski, D Poteryaev, VL Katanaev. Targeting the Wnt pathways for therapies. Mol Cell Ther 2 (2014): 28.
20. H Bazzi, KA Fantauzzo, GD Richardson, et al. The Wnt inhibitor, Dickkopf 4, is induced by canonical Wnt signaling during ectodermal appendage morphogenesis. Dev Biol 305 (2007): 498-507.
21. TS Purba, IS Haslam, E Poblet, et al. Human epithelial hair follicle stem cells and their progeny: Current state of knowledge, the widening gap in translational research and future challenges. BioEssays 36 (2014): 513-525.
22. K Inoue, N Aoi, T Sato, et al. Differential expression of stem-cell-associated markers in human hair follicle epithelial cells. Laboratory Investigation 89 (2009): 844-856.
23. KJ McElwee, S Kissling, E Wenzel, et al. Cultured Peribulbar Dermal Sheath Cells Can Induce Hair Follicle Development and Contribute to the Dermal Sheath and Dermal Papilla. Journal of Investigative Dermatology 121 (2003): 1267-1275.
24. SH Lee, J Yoon, SH Shin, et al. Valproic Acid Induces Hair Regeneration in Murine Model and Activates Alkaline Phosphatase Activity in Human Dermal Papilla Cells. PLoS One 7 (2012): e34152.
25. XM Hu, ZX Li, DY Zhang, et al. A systematic summary of survival and death signalling during the life of hair follicle stem cells. Stem Cell Res Ther 12 (2021): 453.
26. P Zhang, RE Kling, SK Ravuri, et al. A review of adipocyte lineage cells and dermal papilla cells in hair follicle regeneration. J Tissue Eng 5 (2014): 204173141455685.
27. P Gentile, S Garcovich. Advances in Regenerative Stem Cell Therapy in Androgenic Alopecia and Hair Loss: Wnt Pathway, Growth-Factor, and Mesenchymal Stem Cell Signaling Impact Analysis on Cell Growth and Hair Follicle Development. Cells 8 (2019): 466.
28. IH Elmaadawi, BM Mohamed, ZAS Ibrahim, et al. Stem cell therapy as a novel therapeutic intervention for resistant cases of alopecia areata and androgenetic alopecia. Journal of Dermatological Treatment 29 (2018): 431-440.
29. JW Oh, J Kloepper, EA Langan, et al. A Guide to Studying Human Hair Follicle Cycling In Vivo. Journal of Investigative Dermatology 136 (2016): 34-44.
30. KS Yoram Milner, James Sudnik, Mario Filippi, et al. Exogen, Shedding Phase of the Hair Growth Cycle: Characterization of a Mouse Model. J Invest Dermatol 119 (2002): 639-644.
31. S Tanimura, Y Tadokoro, K Inomata, et al. Hair Follicle Stem Cells Provide a Functional Niche for Melanocyte Stem Cells. Cell Stem Cell 8 (2011): 177-187.
32. G Guasch. The Epithelial Stem Cell Niche in Skin, in: Biology and Engineering of Stem Cell Niches, Elsevier (2017): 127-143.
33. P Rompolas, V Greco. Stem cell dynamics in the hair follicle niche. Semin Cell Dev Biol 26 (2014): 34-42.
34. L Zhou, H Wang, J Jing, et al. Regulation of hair follicle development by exosomes derived from dermal papilla cells. Biochem. Biophys. Res. Commun 500 (2018): 325-332.
35. JS Goldberg, KK Hirschi. Diverse roles of the vasculature within the neural stem cell niche. Regenerative Med 4 (2009): 879-897.
36. MV Gómez-Gaviro, CE Scott, AK Sesay, et al. Betacellulin promotes cell proliferation in the neural stem cell niche and stimulates neurogenesis. Proceedings of the National Academy of Sciences 109 (2012): 1317-1322.
37. JR Perlin, A Sporrij, LIZ on. Blood on the tracks: hematopoietic stem cell-endothelial cell interactions in homing and engraftment. J Mol Med 95 (2017): 809-819.
38. OJ Tamplin, EM Durand, LA Carr, et al. Hematopoietic Stem Cell Arrival Triggers Dynamic Remodeling of the Perivascular Niche. Cell 160 (2015): 241-252.
39. G Cotsarelis. Epithelial Stem Cells: A Folliculo-centric View. Journal of Investigative Dermatology 126 (2006): 1459-1468.
40. J Goldstein, V Horsley. Home sweet home: skin stem cell niches. Cellular and Molecular Life Sciences 69 (2012): 2573-2582.
41. YV Zhang, J Cheong, N Ciapurin, et al. Distinct Self-Renewal and Differentiation Phases in the Niche of Infrequently Dividing Hair Follicle Stem Cells. Cell Stem Cell 5 (2009): 267-278.
42. YV Zhang, BS White, DI Shalloway, et al. Stem cell dynamics in mouse hair follicles: A story from cell division counting and single cell lineage tracing. Cell Cycle 9 (2010): 1504-1510.
43. L Zhuang, KT Lawlor, H Schlueter, et al. Pericytes promote skin regeneration by inducing epidermal cell polarity and planar cell divisions. Life Sci Alliance 1 (2018): e201700009.
44. Y Xiao, WM Woo, K Nagao, et al. Perivascular Hair Follicle Stem Cells Associate with a Venule Annulus. Journal of Investigative Dermatology 133 (2013): 2324-2331.
45. L Mecklenburg, DJ Tobin, S Müller-Röver, et al. Active Hair Growth (Anagen) is Associated with Angiogenesis. Journal of Investigative Dermatology 114 (2000): 909-916.
46. K Yano, LF Brown, M Detmar. Control of hair growth and follicle size by VEGF-mediated angiogenesis. Journal of Clinical Investigation 107 (2001): 409-417.
47. WA Marshall, JM Tanner. Variations in the Pattern of Pubertal Changes in Boys. Arch Dis Child 45 (1970): 13-23.
48. WA Marshall, JM Tanner. Variations in pattern of pubertal changes in girls. Arch Dis Child 44 (1969): 291-303.
49. AC Heath, DR Nyholt, NA Gillespie, et al. Genetic Basis of Male Pattern Baldness. Journal of Investigative Dermatology 121 (2003): 1561-1564.
50. R Azziz. The evaluation and management of hirsutism*1. Obstetrics & Gynecology 101 (2003): 995-1007.
51. MJ Thornton, I Laing, K Hamada, et al. Differences in testosterone metabolism by beard and scalp hair follicle dermal papilla cells. Clin Endocrinol (Oxf) 39 (1993): 633-639.
52. VA Randall, NA Hibberts, MJ Thornton, et al. The Hair Follicle: A Paradoxical Androgen Target Organ. Horm Res Paediatr 54 (2000): 243-250.
53. N Hibberts, A Howell, V Randall. Balding hair follicle dermal papilla cells contain higher levels of androgen receptors than those from non-balding scalp. Journal of Endocrinology 156 (1998): 59-65.
54. Y Ando, Y Yamaguchi, K Hamada, et al. Expression of mRNA for androgen receptor, 5alpha-reductase and 17beta-hydroxysteroid dehydrogenase in human dermal papilla cells. British Journal of Dermatology 141 (1999): 840-845.
55. R Choudhry, MB Hodgins, TH Van der Kwast, et al. Localization of androgen receptors in human skin by immunohistochemistry: implications for the hormonal regulation of hair growth, sebaceous glands and sweat glands. Journal of Endocrinology 133 (1992): 467-NP.
56. JJ Lai, P Chang, KP Lai, et al. The role of androgen and androgen receptor in skin-related disorders. Arch Dermatol Res 304 (2012): 499-510.
57. Y Shwartz, M Gonzalez-Celeiro, CL Chen, et al. Cell Types Promoting Goosebumps Form a Niche to Regulate Hair Follicle Stem Cells. Cell 182 (2020): 578-593.e19.
58. D Talavera-Adame, D Newman, N Newman. Conventional and novel stem cell based therapies for androgenic alopecia. Stem Cells Cloning 10 (2017): 11-19.
59. Y Ito, TS Hamazaki, K Ohnuma, et al. Isolation of Murine Hair-Inducing Cells Using the Cell Surface Marker Prominin-1/CD133. Journal of Investigative Dermatology 127 (2007): 1052-1060.
60. K Asakawa, K Toyoshima, N Ishibashi, et al. Hair organ regeneration via the bioengineered hair follicular unit transplantation. Sci Rep 2 (2012): 424.
61. ME Balañá. Epidermal stem cells and skin tissue engineering in hair follicle regeneration. World J Stem Cells 7 (2015): 711.
62. Y Reisner, L Itzicovitch, A Meshorer, et al. Hemopoietic stem cell transplantation using mouse bone marrow and spleen cells fractionated by lectins. Proceedings of the National Academy of Sciences 75 (1978): 2933-2936.
63. H Oshima, A Rochat, C Kedzia, et al. Morphogenesis and Renewal of Hair Follicles from Adult Multipotent Stem Cells. Cell 104 (2001): 233-245.
64. JR Merok, JL Sherley. Breaching the Kinetic Barrier to in Vitro Somatic Stem Cell Propagation. J Biomed Biotechnol 1 (2001): 25-27.
65. L Rambhatla, SA Bohn, PB Stadler, et al. Cellular Senescence: Ex Vivo p53-Dependent Asymmetric Cell Kinetics. J Biomed Biotechnol 1 (2001): 28-37.
66. JL Sherley. Asymmetric Cell Kinetics Genes: The Key to Expansion of Adult Stem Cells in Culture. Stem Cells 20 (2002): 561-572.
67. E Fuchs, JA Segre. Stem Cells. Cell 100 (2000): 143-155.
68. AT Talebzadeh, N Talebzadeh. Stem Cell Applications in Human Hair Growth: A Literature Review. Cureus (2023).