Development, Structure, and Function of Hair Follicles and Hair-associated Disorders: Insights from Men and Mouse

Development, structure, and function of hair follicles and hair-associated disorders: Insights from men and mouse

Abstract

Hair is a remarkable entity with diverse functions in mammals. Over the past many years, hair loss has been a prime anxiety afflicting men. Since then, understanding the biology of hair has laid the foundations for the growth of a multibillion-dollar pharmaceutical/cosmetic industry. Changing dietary patterns, poor interaction with surroundings, and a resulting passive lifestyle has rendered modern society to accrue several factors which have been implicated in hair loss. Besides, genetic composition is considered as one of the most significant factors to determine hair structure, size, color, quality, distribution etc. Here we review the development, morphology, structure and functional aspects of hair shaft and hair follicles and the underlying molecular signalling mechanisms. We have focused on genetic disorders that cause hair loss in mouse and men. This information is valuable for the development of strategies to treat hair loss disorders and to research personnel working on epidermal appendage development.

Hair: minor significance or major impact?

“Hair,” which is thought to be of superficial value, indeed has several crucial functions. It provides thermal regulation in mammals [1], offers protection against several agents including ultraviolet radiation, dust, airborne debris and bugs (eg. hairs of the skin, eye, nose and ear) and maintains the functioning of sensory organs  (hairs in the auditory canal participate in hearing, hairs on the skin acts as a peripheral sensor of touch) [2, 3]. Further, hair acts as an indication of warning or mating by communicative displays to neighbours or opposite gender, respectively, enhances the physical appearance, and reflects reproductive maturity with respect to development of secondary sexual hairs [4] Under certain circumstances, hair acts as an indicator of clan, ancestry or ethnicity [5]. In this context, it should be highlighted that mouse geneticists use coat color to identify different strains and transgenic organisms [6]. Another presumable role for hair in mice is protection against frictional stresses [7]. Occasionally, hair also helps in predator-escape by camouflage (eg: artic fox, artic hare and caribou). Thus, hair is of immense significance and in fact, the anxiety of  hair loss in humans has triggered cosmetic businesspersons to make an annual profit of several billion dollars (http://www.statista.com/statistics/254608/global-hair-care-market-size/).

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Apart from the above-mentioned in situ functions of hair, human kind has put this natural fiber to use in many different ways. Among the plenty of practical applications, quite apparent is the use of animal hairs – wool and fur – in clothing even from the age of Neanderthal. (Braaten, Ann W. (2005). “Wool”. In Steele, Valerie. Encyclopedia of Clothing and Fashion. 3. Thomson Gale. pp. 441–443. ISBN 0-684-31394-4.). Other notable applications are the use of animal hairs in manufacturing felted crafts, blankets, bed, other home furniture, upholstery, brush industry, pet hairs to develop vaccine against allergies, in aesthetic jewellery etc. Both human and animal hair are used as an environmental clean-up agent, especially to clear oil spills due to their great absorbent nature, as compost to enrich the nitrogen content of soil, as a stuffing material for pillows and other insulated threads.

The hair in its details:

The term ‘hair’ not only includes the apparent ‘hair filament’ or ‘hair shaft’ that protrude out of the skin but also the part that lies within the dermis denoted as ‘hair follicle’. The follicle is responsible for regrowth of the hair filament when it breaks, sheds, pulled or plucked-off. A cross-section of the hair shaft has revealed the existence of 3 distinct concentric layers namely medulla, cortex and cuticle [8, 9]. The medulla is the innermost central layer of the hair, while the cuticle is the transparent outer layer made up of scales;  the cortex lies in-between and it contains the melanin pigments (Figure 1) [8, 9]. However, when the hair follicle is sectioned longitudinally, one can observe the existence of 5 additional layers exterior to the hair shaft and within the dermis (Figure 2). These are (i) the Henley’s layer – a thin pale epithelial stratum, (ii) the Huxley’s layer – a thin granular epithelial stratum, (iii) another cuticle (together, these three layers called as the Internal Root Sheath – IRS), (iv) the External Root Sheath (ERS) – an epithelium composed of several cell layers that wraps around the follicle and is contiguous with the epidermis and finally, (v) the connective tissue sheath of the dermis (also known as the dermal root sheath – DRS) that covers the ERS [8, 9].  Inside the follicle, the hair shaft emerges from a bulb-shaped structure called the “hair bulb,” wherein the Henle’s and Huxley’s layer merge and become indistinguishable and so does the IRS and ERS to form an undifferentiated group of cells denoted the “hair matrix” [8, 9]. Melanin pigments and cell mitoses are obvious features of the hair matrix. The connective tissue sheath forms a pear shaped structure called the ‘dermal papilla’ that contains numerous fibroblasts, collagen fibers, and blood capillaries for nourishing the growing and differentiating cells of the attached hair bulb [8, 9]. Two other structures found generally associated with the hair follicle are the ‘arrector pili’ and the ‘sebaceous gland’. Arrector pili is a small, smooth, mesenchyme-derived muscle usually attached to the DRS. The contraction of these muscles in response to cold, fear or other strong emotions causes the hairs to stand on end (piloerection), known colloquially as goose bumps. Notably, arrector pili is poorly developed in hair of the axilla and is absent in hairs of the eyebrows and eyelashes (cilia). Sebaceous gland is a bud like protrusion of the epithelial wall of the hair follicle into the surrounding mesoderm; the central region of the bud degenerate to produce a fat-like substance known as the sebum. (Chapter 21: Integumentary System from Langman’s Medical Embryology Twelfth Edition by T.W. Sadler, 2012, pp. 341).

The evolution of hair

The emergence and evolution of various epidermal appendages, especially hair, has long been a debatable topic owing to several schools of thoughts. Some of these are based on the functions of hair suggesting that it might have originated to fulfill tactile and sensory functions, to protect the skin from different pathogens and to insulate the body from surroundings, as an anchor for holding the vernix caseosa on the skin until birth (Keith L. Moore, chapter 18, Pg.379) etc. A convincing postulate is the gradual evolution of reptilian scales into hairs and feathers [10]. However, lack of evidence in this aspect has driven researchers to explore in different directions and one such group (Dhouailly et al) propose the emergence of hair/feathers to various glands [10]. Recent advancements show that variation in expression of wnt/beta-catenin pathway gives rise to footpads, glands, and hairs or feathers [11-14]. The absence of this signaling pathway corresponds to the corneal epithelium; low levels correspond to the emergence of glands while high levels correlate with the establishment of hairs or feathers. Further, activation of beta-catenin and inhibition of BMP are found to form hair follicles instead of sweat or mammary glands and vice versa [15-17]. Therefore, it is now hypothesized that the synapsid lineage upon separating from the amniotes evolved a glandular integument rather than a scaled one [10]. In line with this, living representatives of the synapsid lineage show a transitional progression among hair and glandular structures, for example, monotremes are found to have mammary glands associated with hair follicles which are observed to be transiently retained in marsupial embryos [18] and finally lost in eutherian embryos. Further, dermatological observations hypothesize the evolution of hair from sebaceous glands [19] wherein the hair shaft serve as capillaries to transport the product of the sebaceous glands to the skin surface thereby mediating insulation and maintenance of water levels. This can be understood in parallel with the emergence of the mammary gland from ancestral sebaceous glands in the present day living monotremes which have associated hairs required to feed its young ones [10].

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Finally, in spite of the presence of a well-preserved and enormous fossil evidence, comprehending the evolutionary trajectory of hair has been an extremely tedious job. Several theories are put forward in this regard but all of them have their own critics.

The emergence of hair:

Hair formation begins when a cluster of basal epidermal cells proliferates and extends downward into the dermis as a bud (epidermal placode).  The process of hair bud formation is influenced by mesenchymal fibroblast cells that team up below the placode to form an aggregate known as ‘dermal condensate (DC)’. The epidermal placode continues to grow downward at an oblique angle, forming the “hair germ,” which later gives rise to the early hair peg. Over time, the terminal end of the hair peg assumes a bulbous club-shaped structure that is invaginated by some of the mesenchymal cells in the DC to give rise to the dermal papilla (DP). Also, melanoblasts migrate into the hair bulbs to differentiate into melanocytes. The cells of the DC that do not invaginate the hair bulb form the papillary pad, which remains connected with the DP by a neck that narrows progressively towards the proximity of the pad. The DP gives rise to the blood vessels and nerve endings of the hair follicle while the pad differentiates into the DRS and arrector pili. Meanwhile, the epidermal cells in the centre of the hair peg and directly above the DP produce the matrix cells, which continuously proliferates and differentiates into a cone of spindle-shaped cells that eventually keratinize and is pushed upward to form the hair shaft. The melanin pigment produced by the melanocytes is transferred to the matrix cells several weeks before birth, thus effecting hair colour. The cuboidal shaped peripheral cells of the hair peg give rise to the epithelial hair sheath (IRS and ERS) and to the sebaceous gland. These glands secrete sebum into the hair follicle that finally reaches the skin. In light of the above, the hair follicle can be essentially considered as a product of proliferation and a unique series of differentiation stages of localized keratinocytes [7, 20].

The first hair, known as lanugo hairs, appear by the end of third month on the eyebrows, upper lip and chin and become plentiful by 17-20 weeks; they help to hold the vernix of the skin. At the time of birth, the lanugo is shed and is replaced by coarser hairs arising from new hair follicles.

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Genetic signaling behind genesis and formation of hair

Epithelial–mesenchymal interaction and pattern formation are the two distinct crucial processes that underlie folliculogenesis and hair shaft development. Several signaling pathways collaborate amongst one another to achieve this evolutionary novelty and understanding the underlying mechanisms hold the answers for not only hair follicle development/regeneration, but also regeneration of the epidermis, wound healing and even the etiological underpinnings of many epidermal neoplasia [121]. Genetic signaling involving hair follicle morphogenesis can be divided into three significant events, which can be elaborated as follows.

Hair follicle induction and placode formation

Hair follicle formation arises through a complex cross talk occurring between dermal cells and their overlying epithelial cells {Schmidt-Ullrich, 2005 #103}. Experiments in mouse and chicken has established that dermis from hair-bearing regions, if combined with epidermis devoid of hair, would induce skin appendage development characteristic of the region of dermis [122]. This provides evidence for a primary signal emanating from the dermis and such a signal instructs the overlying epithelium to aggregate and form a hair placode. However, molecular nature of such a signaling is highly mutable and several studies have outlined the involvement of Wnt/β-catenin pathway, EDA/EDAR/NF-kB pathway and transcription factors like Msx-1&2 in placode formation and maintenance (Gat et al., 1998; Andl et al., 2002) [123][124][125].

Placode inhibitory signals and patterning

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In contrast to placode forming signals, placode inhibiting signals play a vital role to avoid the formation of ectopic placodes or even several skin related tumors. Interaction between placode forming/activators (Wnt 10b, β-catenin, follistatin, Noggin and Gremlin) and inhibiting signals (BMP and Dkk4) lead to the establishment of a regular array of placodes4. Ectopic expression of BMP 2 & 4 is found to suppress feather buds in chick embryos suggesting their role in HF repression and pattern formation [126, 127]. Ectopic expression of the Wnt/b-catenin inhibitor, DKK1, causes blockage of hair follicle induction whereas constitutive activation of Wnt/b-catenin results in stimulation. Also, null- and loss of function- mutations in proteins of the Wnt signalling cascade results in a complete or partial shutdown of HF formation [123] owing to its significance during several different HF stages.

Such a hypothesis was initially proposed by Turing as early as 19525, suggesting the interaction of counteracting morphogens – activators and inhibitors – which interact to generate self-organizing de novo patterns of epidermal appendages. Recently, Sick et al. 2006 utilized both experimental and computational modeling approach to show that WNT and its inhibitor DKK determine the spacing of murine hair follicles (Sick, 2006 #74). Simultaneously, by utilizing a Frizzled6 Knockout mice, Wang et al. demonstrated the existence of two different systems that determine the orientation of a hair follicle depending upon the average orientation of the neighboring hair follicles (Wang, 2006 #75).

Organogenesis and Induction of dermal condensate

Dermal condensation simultaneously parallels placode proliferation and hence both of these events are precisely interdependent in contributing to the development of HF [128]. The condensation/maturation of dermal fibroblasts depends upon signals emanating from the overlying placodal cells. PDGF-A released by the placodal cells communicate with its receptor PDGFR present in the underlying dermal fibroblast cells thereby mediating dermal condensation [129]. The absence of PDGF-A leads to the formation of a small dermal papillae, thin hair and dermal sheath abnormalities in mice, indicating their significance in dermal condensation and maintenance [129]. Another significant signaling pathway mediating cross talk between placodal cells and dermal fibroblast cells is FGF signalling [130]. Fgf20 and Shh expressed in hair placodes [121, 139] is induced by epithelial Wnt/ β-catenin & EDA/EDAR/NF- kB signalling [140]. Fgf20 interacts with its receptor Fgfr1 expressed in the upper dermal cells to mediate dermal condensation [131] while  Shh activates the expression of cyclin D1 which contribute to epithelial placode proliferation and it’s down growth [136-138]. Epithelial Shh induction further drives DP maturation via regulation of dermal Noggin. Activation of Noggin via Shh involves a complex epithelial mesenchymal cross-talk which includes epithelial laminin 511 and mesenchymal dermal β-integrin interaction resulting in the formation of primary cilia which in turn induces epithelial Shh to activate its downstream effector proteins like Ptc, smo and gli. Shh signaling in combination with PDGF signaling activates dermal noggin secretion, thereby inhibiting dermal BMP and hence DP maturation [141].

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Sonic hedgehog is a central key player which mediates epithelial follicle down growth and maturation of dermal condensate15,16,17.

Organogenesis and Induction of dermal condensate

These simultaneous processes (placode proliferation to form the epidermal follicle, and maturation of dermal condensate to form the dermal papilla) give rise to mature HF which additionally requires the antagonistic action of BMP as well [128].

Signaling molecules like Noggin, follistatin, and gremlin mediate BMP inhibition and further contribute to HF formation [26, 132-135]. Sonic hedgehog is a central key player which mediates epithelial follicle down growth and maturation of dermal condensate.

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Cytodifferentiation

Succeeding HF formation, its differentiation is closely regulated by Notch, Wnt and Bmp signaling pathways. The immature HF differentiates into at least 7 different epithelial cell layers giving rise to the mature HF [142]. Notch, a membrane-bound signaling protein with its ligand serrate 1 & 2 regulates differentiation mainly in the epidermis [143], its effector proteins like Wnt5a & FoxN1 regulate HF keratinocyte differentiation & signal specific pigment transfer from melanocytes to keratinocytes of the mature hair cortex [144].

DP directly regulates differentiation of hair shaft progenitor cells through facilitating expression of Sox2. Sox2 modulates hair growth by regulating HF progenitor cell migration. This is achieved by upregulating BMP6 (inhibitor of cell migration) and upregulating Sostdc1 (inhibitor of Bmp) [143]. Bmp with its receptor BMPIA is further implicated in epithelial stem cell maintenance, hair shaft progenitor differentiation, and DP cell maintenance. This is achieved by activation of GATA3 which in turn regulates Bmp levels [145]. Further, several studies have identified transcription factors like Msx2, FoxN1 and Hoxc13 and BMP signaling to regulate hair shaft differentiation [146-151] while transcription factors like Gata3 and Cut1 in regulating IRS differentiation [152-154].

Hair follicles are found in regularly spaced arrays, with large primary hair follicles being interspersed by smaller follicles throughout the skin. In addition, there exists a marked difference in length, texture, and growth of the hair in different regions of the body (scalp, axilla etc.). Pattern formation is responsible for this regular pattern and the anterior-posterior orientation of hair follicles, but the mechanisms that underlie the generation of such patterns remain poorly understood in humans. However, epidermal appendage patterning is more pronounced in animals where it determines the dorsoventral patterning, cranial hair patterning, formation of vibrissae and tail hairs and therefore much work in mouse models has provided accountable information on this process  [21]. Turing, in 1952 [22], suggested a model (Reaction-Diffusion model; in short, RD model) that involved two different types of morphogens – activators and inhibitors – which interact to generate self-organizing de novo patterns of epidermal appendages. Since then, a number of studies have attempted to simplify/extend Turing’s RD model to explain the patterning of hair follicles in regular arrays wherein activators determine the size of the follicle domain, while inhibitors define follicle spacing [23-25].   Molecular developmental studies have shown that Fgf4, follistatin, noggin, and Shh areactivators of follicle development, while BMPs are follicle inhibitors [26-28]. The follicle inhibitors have greater diffusion capabilities and are active in the interfollicular space where they suppress follicle development while the locally acting follicle activators counteract the inhibitory signal giving rise to hair follicle morphogenesis. More recently, Sick et al. 2006 utilized both experimental and computational modeling approach to show that WNT and its inhibitor DKK determine the spacing of murine hair follicles thus strongly supporting the RD mechanism [29]. Simultaneously, by utilizing a Frizzled6 knockout mice, Wang et al. demonstrated the existence of two different systems that determine the orientation of a hair follicle depending on the average orientation of the neighbouring hair follicles: a global orientating system that acts early in development and is Fz6-dependent, and a local orienting system that is Fz6-independent and acts later. Further, this study showed the importance of planar cell polarity signaling in directing the orientation of hair follicle [30]. Thus, a well-timed interaction among various different cell signaling pathways results in the formation of properly oriented and spaced hairs.

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Types of Hair in Mice and Men

The basic structure of skin and associated epidermal appendages is generally similar in both mice and men, with some regional exceptions and differences in size, the density of hair follicles, distribution etc (Table ???). At the outset, the mouse has pelage (hair coat) and a tail, unlike humans. The mouse pelage is composed of four distinct types of hairs namely, guard-, awl-, auschene- and zigzag hairs that differ in their length and morphology.  The mouse-tail epidermis is thicker and has relatively sparse hair follicles compared to the pelage, while the muzzle skin has specialized hairs known as ‘vibrissae’, which serves as a somatosensory organ. Perianal hairs and specialized sebaceous glands are also found in the mouse genital region. In humans, two types of body hairs can be seen, viz a viz, the fine ‘vellus’ and thick ‘terminal’ hairs. Humans lack vibrissae, but males do possess whiskers, a form of terminal hair on the face. Like human palms and soles, the mouse footpads are devoid of hair and in both cases, the epidermis is markedly thickened. However, mice have relatively smooth plantar and palmar surfaces on their footpads in contrast to the fingerprints of humans (rete ridges and pegs exacerbated in the palms, soles, and digits). The human axilla contains both apocrine and eccrine sweat glands; mice has eccrine sweat glands exclusively present in the pads of their paws, and its trunk skin lacks sweat glands altogether.