Hair Follicles Are Made of a Downward Continuation of the Epidermis Called the

Hair Follicle

The hair follicle (HF) has several stem cell compartments that are tightly regulated in order to orchestrate the hair cycle, whereby each follicle undergoes phases of growth (anagen), regression (catagen) and rest (telogen) throughout the life of the mammal.

From: Advances in Stem Cells and their Niches , 2019

Skin and Skin Appendage Regeneration

Krzysztof Kobielak , ... Yvonne Leung , in Translational Regenerative Medicine, 2015

Hair Follicle and Sebaceous Gland 276

Hair Follicle and Sebaceous Gland Structure and Function276

Hair Follicle Stem Cells (HFSCs)276

Hair Germ (HG)278

Role of Hair Follicles in Skin Regeneration278

Niche Components of Hair Follicle Stem Cells and Hair Germ279

The Dermal Papillae and Dermal Sheath279

Subcutaneous Adipocytes and Adipocyte Precursors279

Inner Layer of Bulge Cells279

Additional Components of the Hair Follicle Niche280

Intrinsic (Intrabulge) and Extrinsic (Niche Environment) Signaling in Hair Follicle Stem Cells and Hair Regeneration280

Intra-Stem Cell Antagonistic Competition between BMP and Wnt Signaling Balances Stem Cell Activity282

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Cutaneous Autonomic Innervation

Christopher H. Gibbons , Roy Freeman , in Primer on the Autonomic Nervous System (Third Edition), 2012

Hair Follicles

Hair follicles extend from the deeper dermal tissue, through the basement membrane and epithelial layer and extend beyond the border of the skin. The base of the hair follicle is deep within the dermal tissue, the hair follicle itself is anchored to the skin by arrector pili muscles and sebaceous glands. Hair follicles have large numbers of sensory fibers that circumferentially wrap around the base of the follicle and extend up the shaft in order to provide sensory feedback. The majority of the innervation to the hair follicle is sensory. Autonomic nerve fibers also innervate the base of the hair follicle. The innervation is primarily sympathetic cholinergic but there are some sympathetic adrenergic fibers noted as well. To date, there have been no efforts to quantify the density of sensory or autonomic nerve fibers around hair follicles.

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Aging and Anti-Aging in Hair and Hair Loss

Chao-Chun Yang , ... Wen-Chieh Chen , in Inflammation, Advancing Age and Nutrition, 2014

Neurogenic Inflammation

Hair follicles incubated with corticotropin-releasing hormone, a key stress hormone, show strong mast cell degranulation in the connective tissue sheath and interfollicular dermis [56]. Degranulation of mast cells is associated with the induction of catagen in hair follicles. Stress can also trigger mast cell-dependent neurogenic inflammation around the hair follicles through the release of substance P (SP) from nerve endings [57]. SP, a stress-associated neuropeptide expressed in the skin, also upregulates MHC [major histocompatibility complex; more correctly, histocompatibility antigen (HLA)] class I and β2-microglobulin expression in hair follicle epithelium. These data suggest that in alopecia areata (AA) and scarring alopecia stress-associated collapse in hair follicle immune privilege renders affected hair follicles susceptible to immunological attack [58].

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Hair Follicle-Associated Pluripotent(HAP) Stem Cells

Robert M. Hoffman , Yasuyuki Amoh , in Progress in Molecular Biology and Translational Science, 2018

Abstract

The hair follicle has been known, since 1990, to contain stem cells located in the bulge area. In 2003, we reported a new type of stem cell in the hair follicle that expresses the brain stem-cell marker nestin. We have termed these cells as hair-follicle-associated pluripotent (HAP) stem cells. HAP stem cells can differentiate into neuronal and glial cells, beating cardiac-muscle cells, and other cell types in culture. HAP stem cells can be used for nerve and spinal-cord repair such that locomotor activity is recovered. A major function in situ of the HAP stem cells is for growth of the hair follicle sensory nerve. HAP stem cells have critical advantages over embryonic stem cells and induced pluripotent stem (IPS) cells for regenerative medicine in that they are highly accessible, require no genetic manipulation, are nontumorigenic, and do not present ethical issues.

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Exosomes in cutaneous biology and dermatologic disease

Jeffrey D. McBride , ... Evangelos Badiavas , in Exosomes, 2020

4 The dermis fibroblasts, specifically the dermal papilla cells, secrete exosomes that stimulate hair follicle growth phase, known as the anagen phase

Hair follicle density is critical to skin-bacteria homeostasis, temperature regulation, sexual signaling, and even human cosmetics and self-esteem. Exosomes secreted by dermal papilla cells were found to be important in the development of hair follicles [9]. Dermal papilla cells play a crucial role in the regulation of hair follicle growth, formation and cycling [9]. It was hypothesized that the dermal papilla regulated hair follicle growth via paracrine mechanisms, in part via exosomes [9]. In this study, hair follicles at different stages of cycling were injected with exosomes derived from dermal papilla cells, which expressed CD9, CD63, and TSG101 [9]. The effects of the exosomes on outer root sheath cells proliferation, migration and cell cycle status were evaluated [9]. Dermal papilla cells-derived exosomes accelerated the onset of hair follicle transition from telogen (resting phase) to anagen phase (the follicle growth phase) and delayed catagen (the follicle breakdown phase) in mice [9]. Exosomes upregulated both beta-catenin and Shh levels in the hair follicle and increased outer root sheet proliferation and migration [9]. Thus, it is likely that the developing hair follicle is stimulated from exosomes from the dermal papilla that stimulate the Wnt/beta-catenin signaling pathways and the sonic hedgehog pathway [9]. Thus, exosomes from fibroblasts stimulate the growth of hair follicles, critical for skin homeostasis.

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In vitro models to study hair follicle generation

Ana Korosec , Beate M. Lichtenberger , in Skin Tissue Models, 2018

2 Hair follicle morphogenesis

HF organogenesis occurs early during embryonic development with the appearance of dermal cells toward the end of the first trimester [3,37]. In mice, HFs develop in waves from embryonic day 12.5 to 18.5 and result in a number of different hair types: primary or tylotrich (guard) HFs, characterized by huge hair bulbs, long straight hair, and two sebaceous glands; secondary or nontylotrich (awl, auchene, and zigzag) HFs with thinner and shorter HSs and one sebaceous gland; and vibrissae HFs with specialized sensory functions [37]. HF morphogenesis depends on reciprocal signaling between epidermal stem cells and specialized cells of the underlying mesenchyme, which aggregate forming the dermal condensate (DC) and will later become the dermal papilla (DP, Fig. 1) of the HF [7]. Dermal signals induce a focal thickening in the basal layer of the epidermis (hair germ or hair placode) and stimulate epidermal stem cells to grow downward and invaginate into the dermis, thereby engulfing the cells of the DC, which leads to the formation of the DP (Figs. 1 and 2A ) and further drives HF formation [37]. As the follicle grows downward, it is encapsuled by the highly proliferative, transit-amplifying matrix cells at the leading edge. The formation of the HF lumen is mediated by early outward movement of keratin 79 (K79) epidermal cells from within the cores of developing hair buds and into the epidermis [38]. The inner layers of the HF differentiate into concentric cylinders and generate the inner root sheath (IRS) and the central HS, while the outer root sheath (ORS) is continuous with the basal layer of the interfollicular epidermis (IFE). The IRS cells migrate outward from the base of the hair buds. Subsequently, K79⁺ cells are lost from the epidermis, thereby leaving behind a gap above the future site of the hair canal [38]. Once the HF reaches the bottom of the dermis, the HF becomes fully mature. However, matrix cells continue dividing, and their successors terminally differentiate to form the growing hair that exits the skin surface. In the mouse back skin, HF morphogenesis is completed between postnatal days 6 and 8 [37,39,40]. The ability of the HF to regenerate is due to the presence of a pool of stem cells located in the bulge region of the HF, which forms a special niche that is critical for controlling SC self-renewal and thus the process of regeneration [41]. Bulge stem cell identity specification occurs early during HF morphogenesis in the embryo [41].

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Strategies to utilize iPS cells for hair follicle regeneration and the treatment of hair loss disorders

Manabu Ohyama , in Recent Advances in iPSCs for Therapy, Volume 3, 2021

Abstract

The hair follicle (HF) is a mammalian skin structure that provides physical protection, detects sensation, and enables thermoregulation. In humans, loss of hairs on the head greatly affects the physical appearance, leading to altered quality of life. Thus, vast demand exists for treatments for hair loss disorders, represented by male and female pattern hair loss or alopecia areata. Regenerative medicine approaches, including HF bioengineering, can provide remedies for intractable hair loss diseases caused by irreversible HF destruction. The basis for experimental HF regeneration has been established in murine. However, human HF reconstitution adopting that principle has been hampered by the paucity of starting materials, including HF epithelial stem cells and hair-inductive dermal cells, and the loss of their HF-prone properties during in vitro expansion. With their high-proliferative capacity and multipotency, human induced pluripotent stem cells (hiPSCs) should be useful for HF regeneration. Indeed, hiPSC-derived epithelial and mesenchymal cells can contribute to in vivo HF-like structure regeneration. hiPSCs can also give rise to 3D integumentary organ systems comprising HFs which can be isolated and grafted onto areas of hair loss. Previous studies have focused mainly on the reproduction of HF structures; however, considering that the regeneration of complete HFs is not required to correct many common hair loss conditions, hiPSCs may be better differentiated into trichogenic dermal cells for cell-based therapy. For immune-mediated hair loss disorders, immunoregulatory cells can be induced from hiPSCs and inoculated into the affected lesion. In summary, hiPSCs are a promising cell source not only for HF bioengineering and but also for preparing cell populations that may be able to mitigate hair loss.

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Epigenetic Modulation of Hair Follicle Stem Cells

Haijing Wu , Qianjin Lu , in Epigenetics and Dermatology, 2015

5.1.3 Applications of HF-SCs

HF-SCs, of course, have been intensively studied for hair regeneration, a cure for hair loss. Until recently there has been no valid treatment for patients. Traditional medicines have promoted hair growth but have failed to generate new HFs in the bald scalp to achieve the ultimate goal of therapy [13]. Therefore, the regenerative power of HF-SCs provides patients with the hope of generating new HFs and being cured.

In addition to the potential in treating hair loss, HF-SCs with nestin expression are found to be multipotent in that the cells can differentiate into keratinocytes, neurons, glia, smooth muscle cells, and melanocytes in vitro. They also contribute to the recovery of peripheral nerve and spinal cord injury, indicating that HF-SCs provide an essentially accessible, autologous source of adult stem cells with the potential for use in regenerative medicine [14]. Moreover, recent studies have suggested that adult tissue-derived follicular stem cells can be used as a potential bioengineered organ replacement therapy to treat damaged organs [15]. Therefore, a well-established understanding of HF-SCs and their differentiation potential may provide a novel strategy for treatments of inherited skin diseases, injury, hair loss, and even neuromuscular and hematopoietic diseases.

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Healthy Hair (Anatomy, Biology, Morphogenesis, Cycling, and Function)

Penelope A. Hirt MD , Ralf Paus MD, FRSB , in Alopecia, 2019

Embryology

In utero, the future distribution and phenotype (long scalp hair and short eyebrow hair) of HFs over the surface of the body is already genetically determined. ⁷ Interestingly, many of the homologs of the molecular signals governing these events in mammals were first discovered in drosophila (fruit flies). ^7–10 The precise spacing and distribution of HF is also established by genes expressed very early in utero, creating gradients of inhibitory and stimulatory molecules, which determine where, and where not, the HFs will develop in the epidermis and which type of HF will grow. ^7–12

Around 5 million HFs are thought to be present in the surface of the body at birth. ⁷ Follicle formation occurs once in a lifetime of an individual, so a mammal is born with a fixed number of HFs. ⁷ However, in exceptional circumstances, for example, after sufficiently large skin wounds, postnatal HF neogenesis is possible in some mammals. ^13,14 Nevertheless, the size of the follicles and the hair shafts they produce can change with time, mostly under the influence of hormones such as androgens. ^7–10,15

Human HF formation begins around the third month of gestation and is initiated in the eyebrow and scalp regions, progressing caudally. ¹⁶ HF development is the result of neuroectodermal–mesodermal interactions and requires input from the HF's distinc stem cell populations epithelial, neural crest, and mesenchymal. ^11,16–18

Early in fetal skin development, specific foci of the primitive epidermis become capable to generate HFs. ¹⁴ The basic requirements for HF development are the interactions between the epidermis and the underlying mesenchyme ^16,19,20 . These requirements are intrinsic to the epidermal-mesenchymal exchanges; hence, HF production does not need intact hormonal or neural circuits. ²⁰ This explains why HFs can develop de novo from organ culture fragments of fetal skin. ^14,21

HFs develop in a periodically patterned manner, with several models having been proposed to explain the spontaneous emergence of such patterns ^11,12 :

Stages of Hair Follicle Formation

HF formation has been divided into eight distinct developmental stages (0–8) ²⁰ (Fig. 1.1). Induction comes from the dermis (stages 0–1); however, while the underlying molecular controls are reasonably well-defined in mice, they remain quite unclear in human fetal skin. ²⁰ The induction process results in the placode formation, followed by organogenesis (stages 2–5) and cytodifferentiation or maturation (stages 6–8), each phase requiring specific molecular interactions. ²⁰

Mesenchymal cell aggregation below the epidermis is one of the first steps in HF formation. ²⁰ Specialized fibroblasts interact with the epidermis and become enlarged and elongated, inducing the focal growth of hair placodes in defined, regularly spaced areas of the overlying epidermis (stages 0–1) (Fig. 1.1). ^7,16,20 The hair placode starts to become morphologically apparent once epidermal keratinocytes start to focally proliferate and assume an upright position to form a small epithelial ingrowth into the dermis. ²⁰ Hair placode formation is followed by condensation of specialized fibroblasts with inductive properties in the underlying mesenchyme. ¹⁶ The interactions between the epithelial hair placode and this mesenchymal condensate induce proliferation in both structures. Hair placode and mesenchymal proliferation stimulate the process of shaping of the follicular dermal papilla (DP) in the mesoderm and the downgrowth of the ectodermal placode. ¹⁶

Stage 2 is characterized by the formation of the hair germ, which occurs due to keratinocyte proliferation, because of cyclin D1 upregulation. ¹⁶ Stages 3–4 result in the peg stage, where the most proximally located keratinocytes begin to enfold the DP, followed by the bulbous peg stage (stage 5–8), when distinct strata of epithelial differentiation within the HF becomes morphologically evident (Fig. 1.1). ¹⁶

As a critical event, during stage 5, HF keratinocytes begin to form a central tube that will differentiate into the inner root sheath (IRS) (Fig. 1.1). ¹⁶ These keratinocytes are the first epithelial cells in the HF that have the ability to terminally differentiate. ¹⁶ In the center of the tube, the hair shaft will originate from terminally differentiated HF keratinocytes, i.e., trichocytes. ¹⁶ The IRS is surrounded by cylindrical layers of outer root sheath (ORS) cells. ¹⁶ The IRS formation is a decisive step in HF morphogenesis, because it is a critical prerequisite for orderly hair shaft formation. ^7,15,16

There are other important events during stage 5, such as the migration of immune cells to the distal follicle epithelium and the perifollicular mesenchyme. ¹⁶ Langerhans cells and T cells migrate to the distal follicular epithelium (predominantly γδ T cells in mice and αβ cells in humans). ¹⁶ Mast cells and macrophages home to the perifollicular mesenchyme, which is the connective tissue sheath (syn.: dermal sheath) of the HF. ¹⁶ Current understanding is that the secretion of chemoattractants, such as interleukin (IL) 8 cytokines, and distinct adhesion molecule expression patterns by HF keratinocytes may play a major role in determining this homing of immunocytes onto the HF. ¹⁶ However, more research needs to be done to better understand how these important events are controlled. Also, during stage 5, melanin production is initiated in the HF pigmentary unit, and keratinocytes in the distal HF epithelium differentiate into sebocytes or precursors of the apocrine gland. ¹⁶

Molecular and Genetic Basis of Hair Follicle Embryogenesis

There are many molecules controlling HF development through the communication of the epidermis and dermis. These include members of the Wnt family, whose activity is tightly controlled by Wnt antagonists such as Dkk-1, sonic hedgehog, as well as members of the transforming growth factor (TGF) β/bone morphogenetic protein (BMP), fibroblast growth factor (FGF), and TNF families. ^{11,12,16,19,20}

Not every epidermal keratinocyte will become a follicular keratinocyte, which results in hairless spaces between the regular arrays of HF. ^11,12,20 This is now known to be controlled by changes in the local gradient of HF activators and inhibitors. ^{11,12,16,20,22} Wnt, Eda-A1, and Noggin are hair placode–inducing signals, whereas BMPs are HF-inhibiting signals. ^12,20

The molecular controls of HF induction and morphogenesis have mostly been studied in mice ¹⁶ ; therefore, caution is advised as to assuming that the very same controls also operate during human HF development. However, it is widely assumed that key regulatory principles are conserved between mammalian species, including human skin, with fundamental pointer to gene relevant in HF development being derived from rare human genetic disorders. ²³

Activation of Wnt signaling is indispensable for the initiation of hair placode formation. ²⁴ In guard hairs, EdaA1/EdaR and transcription factor NF-κB activity induces local epidermal cell proliferation. ^19,25,26 Wnt/β-catenin and Noggin/Lef-1 are responsible for inhibiting the expression of the adhesion molecule E-cadherin; ^16,27 thus, decreasing the local cell adhesion that is necessary for normal placode downgrowth. ^16,28 BMP and Wnt are also important for HF cycle regulation, where these signals tend to have opposite effects. ¹²

At the end of its morphogenesis phase, the HF has a cyclically remodeled inferior (proximal) region, including the bulge, and a "permanent" superficial (distal) region. Nevertheless, it has long been clear that this is an illusion based on simplistic histochemical analyses, because even the so-called "permanent" part of the HF, including the bulge, undergoes significant hair cycle–dependent remodeling events, such as focal apoptosis. ²⁹

Once fully formed, the follicle enters its first genuine cycle. HF cycle begins with a short phase of regression (catagen), followed by a state of relative rest (telogen), and then resumes its production of a hair shaft (anagen). ^20,30 In human HFs, cycling occurs already in utero and the first "test hair shaft" (lanugo hair) is shed into the uterine fluid. On the other hand, in mice, HFs enter into hair cycling only much later, after the first 2 weeks of postnatal life. ²⁹

It is known that during the early postnatal period regulatory T (Treg) cells accumulate in the skin and that germ-free neonates have fewer skin Treg cells. ³¹ Scharschmidt et al. recently showed that HF development induces the accumulation of Treg cells in neonatal mouse skin, which becomes predominantly localized to HFs. ³¹ These authors also observed that commensal microbes augment Treg cell accumulation. ³¹ Ccl20 was identified as an HF-derived, microbiota-dependent chemokine, and its receptor, Ccr6, was found to be expressed by Treg cells in neonatal skin. ³¹ Presumably, this Ccl20-Ccr6 pathway mediates Treg cell migration in vitro and in vivo. ³¹ Together with the recent discovery that Treg cells are actually important regulators of murine HF cycling, ³² introducing Treg cells and their interaction with the skin microbiome as novel regulators of HF cycling in mice, thus joining perifollicular mast cells, macrophages, and γδ T cells, which had previously been shown to regulate murine HF cycling. ^33–35 In spite of, it is yet unclear under which conditions and to which extent these immune cells also contribute to the regulation of human HF cycling.

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Hair Follicles Are Made of a Downward Continuation of the Epidermis Called the

Hair Follicle

Skin and Skin Appendage Regeneration

Cutaneous Autonomic Innervation

Hair Follicles

Aging and Anti-Aging in Hair and Hair Loss

Neurogenic Inflammation

Hair Follicle-Associated Pluripotent(HAP) Stem Cells

Abstract

Exosomes in cutaneous biology and dermatologic disease

4 The dermis fibroblasts, specifically the dermal papilla cells, secrete exosomes that stimulate hair follicle growth phase, known as the anagen phase

In vitro models to study hair follicle generation

2 Hair follicle morphogenesis

Strategies to utilize iPS cells for hair follicle regeneration and the treatment of hair loss disorders

Abstract

Epigenetic Modulation of Hair Follicle Stem Cells

5.1.3 Applications of HF-SCs

Healthy Hair (Anatomy, Biology, Morphogenesis, Cycling, and Function)

Embryology

Stages of Hair Follicle Formation

Molecular and Genetic Basis of Hair Follicle Embryogenesis

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