Chapter 1: Anatomy and Biology of Hair at Different Ages

Hair is a common characteristic of all mammals. Beyond its aesthetic and social properties, it protects the skin from mechanical insults, participates in thermoregulation, and allows the perception of touch to be extended beyond the skin area. Hair is currently considered to be a highly complex functioning “mini-organ”, that presents a continuous cycle of alternating growth and regression phases, in an environment requiring stem cells, surrounding niche components and various signaling pathways.³  This regeneration also affects the pigment compartment that gives hair its colour. To build this complex structure, which is also unique in humans, sophisticated morphogenesis is required during embryonic development.^1–4  The aim of this chapter is to provide a comprehensive understanding of the anatomy and biology of the hair follicle, as well as the mechanisms that control its organogenesis.

Mammalian skin is covered with body hair over almost the entire body surface, with the exception of the sole of the foot, the palm of the hand, the oral side of the lip, and some areas of the external genitalia. These hairs are generally fine, with very little melanization, and grow very slowly. Others, such as head hair, eyelashes, and eyebrows, are longer, more pigmented, and more resistant.¹  From a macrostructural point of view, head hair varies in form (straight, wavy, curly), but also in length, diameter, color, and cross-sectional shape among the different ethnic groups and among singular individuals. While human hair is generally classified according to three conventional ethnic subgroups, namely Africans, Asians and Europeans, de la Mettrie et al. have demonstrated that, due to the great complexity of human biological diversity resulting from both multiple and mixed origins, hair is best classified into eight major types, based on three parameters: curl diameter, curl index, and number of waves.⁵  This method allows a coherent classification applicable in dermatology as well as in forensic sciences and anthropology.

Hair is composed, depending on its moisture content, of approximately 65–95% proteins, 1–9% lipids, 0.1–5% pigments, 0.25–0.95% of trace elements and heavy metals, and water. 80% of hair proteins are made up of keratin, a fibrous protein that contains a high level of amino acids, mainly cysteine, which may be degraded and afterwards may be re-oxidized in a disulphide bonding form, and which gives the hair mechanical resistance, flexibility, durability, and functionality.^6–8 

Hair is divided into two distinct parts: the hair shaft, visible on the surface of the scalp, and the root, which extends obliquely into the epidermal epithelium of the skin to a depth of about 3–4 mm.⁶  The root includes the hair follicle and its appendages, the sweat and sebaceous glands and the arrector muscle, which form the pilosebaceous unit, as well as blood capillaries and nerve endings.²  Surrounded by several layers, the root is embedded in the pilary canal.^1,2,6,9,10 

The hair shaft is composed of 95% dead and fully keratinized epithelial cells, and consists of three concentric layers from the periphery to the core (Figure 1.1). The outer layer, or cuticle, is composed of flattened rectangular cells which overlap the distal direction of the thread. The overlap is arranged so that only 1/6 of them are exposed. There are approximately 8–11 layers of cuticle, each layer consisting of a single cell. Each cell has a rectangular shape, a diameter of about 50–100 µm and a thickness of 0.5 µm.^8,11,12  It is made up, from the periphery to the center, of a thin outer membrane, the epicuticle, about 3 nm long, which is a protein envelope covered with a strong lipid structure; the A layer, mainly composed of cysteine (>30%), which gives the cuticle its resistance to physical and chemical attacks; layer B, or the exocuticle, also rich in cysteine (>15%) and physically rigid; and finally the endocuticle, less rich in cysteine and less rigid than the previous layers, which absorbs water when the hair is wet. The cuticle cells are cemented together by the cellular membrane complex (CMC), rich in essential fatty acids, in particular 18-methyl-eicosanoic acid (18-MEA), which is covalently bound to the proteins of the cuticle cells. 18-MEA is the main lipid in the hair composition contributing to the wet and dry combing properties.^8,13  Recently, Takayashi et al. identified another structure, located under the endocuticle of the innermost cell layer, which would ensure the anchoring of the cuticle to the cortex and protect the latter against external aggression, called CARB, for cuticle anchored resistant base.¹⁴  CARB, rich in cystine and glycolipids, appears at the final stage of keratinization of the cuticular layers.¹⁵ 

The middle layer, or cortex, represents 90% of the total weight of the hair and forms the primary structure of the hair shaft. The elongated, interdigitated, spindle-shaped cortical cells, about 100 µm long and 1–6 µm thick, are merged and aligned or slightly inclined to the direction of the longitudinal axis of the fiber. They are composed of about ten macrofibrils, themselves composed of several hundred intermediate filaments or microfibrils, each microfibril comprising eight protofilaments. Each protofilament contains chains composed of four helices of α-keratin. The cohesion of the filaments is ensured by an interfilamentary matrix, rich in sulfur proteins, called keratin-associated proteins (KAPs). There are more than 100 KAPs grouped into three classes according to their composition (rich in cysteine, ultra-rich in cysteine and rich in glycine–tyrosine). These proteins establish disulphide bonds and hydrophobic interactions with keratin fibers.¹⁶  The arrangement of the fibrils makes it possible to distinguish schematically two types of cortical cells: paracortical cells, the most abundant, present a stack of microfibrils in a compact hexagonal mode, the macrofibrils being fused and practically indistinct, and orthocortical cells, in which the macrofibrils are twisted along the longitudinal axis of the cell, the microfibrils being wound around the periphery of the macrofibrils. Some authors describe mesocortical macrofibrils, intermediate structures between the two previous ones.^8,12,17,18  This complex arrangement of fibrils, held together by KAPs, is essential for the elasticity and strength of the hair. Fibril arrangement varies according to the hair curvature. In straight hairs, all macrofibrils tend to adopt a straight conformation, as wavy hairs are characterized by interlaced orthocortical and mesocortical macrofibrils around paracortical macrofibrils. As the curl degree increases, the mesocortex disappears, leading to a majority of orthocortical cells.¹⁹  The melanin granules, responsible for hair color, are located in the periphery of the cortex.²⁰ 

The inner layer, or medulla, consists of a thin layer of pigmented keratinized cells, often disjointed by small air bubbles. It is abundant in beard hair, inconsistent in hair, and can present solutions of continuity. It does not seem to have any influence on the mechanical properties of the hair.^21,22 

The hair follicle (Figure 1.2) is composed of different clearly individualized compartments: the connective sheath and the dermal papilla, of dermal origin, the external epithelial sheath, the internal sheath, and the hair shaft of epithelial origin. Anatomically, the follicle comprises two main regions, delimited by the isthmus, a short portion located between the duct of the sebaceous gland and the protuberance of the arrector muscle.¹⁰  The supra-isthmic region comprises the infundibulum, which is divided into an upper intra-epidermal part, the acro-infundibulum, and a lower intra-dermal part, the infra-infundibulum. The acro-infundibulum, in communication with the skin surface, is bordered by an epithelium in continuity with the epidermis, including a developed stratum corneum and a stratum granulosum.²  The sub-isthmic region is formed by the hair root and its outer and inner epithelial sheaths. Between the sebaceous gland and the insertion of the arrector muscle, the bulge, considered by some authors as the distal zone of the bulb, is a specialized compartment of the outer root sheath which contains several contingents of totipotent stem cells (see below). One of them will give rise to the keratinocytes of the bulb and interfollicular space, as well as the sebocytes, and another contingent will provide melanocytes.^23–25  The permanent part of the hair follicle, between the surface of the skin and the lower end of the bulb region, does not undergo significant cyclical changes, unlike the lower part of the hair follicle.²  The lower part of the follicle, which extends from the bulge to the base of the bulb, is surrounded by eight concentric sheaths from the periphery to the core:

• The conjunctive sheath, synthesized by fibroblasts, is an extracellular matrix formed of type I and III collagen and proteoglycans. It is in continuous with the dermal papilla and is crossed in its lower part by a capillary loop and by nerve endings.^1,2,10,26 

• The basal membrane, composed of type IV collagen, type 1 laminin, fibronectin, and proteoglycans, separates the dermal compartment from the epithelial compartment. The expression of some of its components such as laminin, is disrupted at the periphery of the bulb.^26,27 

• The outer root sheath, which extends from the matrix cells of the bulb to the orifice of the sebaceous duct, is keratinized from the isthmus. The cells of the outer root sheath express a wide variety of mediators, hormones, and receptors containing melanocytes, as well as Langerhans cells, dendritic cells involved in the immune response, and Merkel cells, rich in neuropeptides.^2,10,28 

• The inner root sheath, itself composed of three distinct layers: Henle’s layer, a bed of cuboidal cells rich in trichohyalin granules, keratinizing early, Huxley’s layer, made up of one or two layers of larger cells, whose keratinization starts above the previous one, and finally the cuticle layer, consisting of a layer of flattened hyalinized cells from the isthmic region.¹  Some authors also recognize the existence of an additional layer, the so-called companion layer, which is single-celled and represents the transition between the outer and inner sheaths, over a length from the bulb to the isthmus.^10,29  According to Vogt et al., it allows the inner root sheath to slide upward over the outer root sheath during hair growth.²  The inner sheath narrows from bottom to top. From the middle of the isthmus, the different layers are merged into a single hyaline layer which disappears at the height of the isthmus. The cells of the inner sheath produce keratins and trichohyalin which serve as intracellular cement to support and shape the growing hair shaft.¹ 

The follicle itself is divided into supra-bulbar and bulbar regions, the latter including the bulb and the dermal papilla.^2,10  The bulb is the portion of the follicle which actively produces the hair. It can be divided by the Auber’s line into two regions. Below the Auber’s line is the matrix, in contact with an expansion of the dermis, the dermal papilla, a mesenchymal invagination rich in densely packed fibroblasts, endothelial cells, hyaluronic acid, and chondroitin sulfate. It receives blood and lymphatic capillaries as well as nerve endings. Fibroblasts of the papilla secrete poorly differentiated matrix cells and anchor the follicle during the anagen phase.^1,10,25  They specifically express a large number of markers and growth factors (keratinocyte growth factor, bone morphogenetic protein, hepatocyte growth factor, insulin-like growth factor, stem cell factor, etc.), which generate complex signals for matrix cell proliferation, migration, and differentiation.^1,2,10  These signaling pathways also determine the size of the bulb, the dimension and curvature of the hair and the duration of the anagen phase (see below). In addition, the fibroblasts of the dermal papilla are thought to act as a reservoir of multipotent stem cells that differentiate into other cell lineages: chondrocytes, osteoblasts, and adipocytes.³⁰  The matrix zone, separated from the papilla by the basal membrane, is itself composed of several zones: the deep fertile zone, the melanocyte zone and the keratogenous zone. The deep fertile zone, in immediate contact with the papilla, is rich in epithelial progenitor cells which will multiply and divide at a very rapid rate during the anagen phase. The cells resulting from these divisions will accumulate keratin and melanosomes in the dedicated regions.³¹  Then they move to the upper part of the bulb, which is divided into four parts. Above the Auber’s line, in the wide portion of the bulb is the pre-elongation region in which the cells align themselves vertically and enlarge. Above the pre-elongation region is the cellular elongation region, narrower than the previous one, where the cells elongate. This zone ends about one third of the way from the tip of the papilla to the skin surface. At the end of this migration, the cells are enriched in keratin and pigments and have lost their nucleus.¹ 

The follicle is, therefore, organized concentrically around a symmetry axis. The shape of the hair (straight, wavy, curly) is the result of an internal tension in the fiber: a follicle associated with a curly hair is characterized by an S-shaped curvature at the bulb, in relation to an asymmetry in the differentiation programs of the different compartments of the bulb, with the matrix cells proliferating more actively on the convex side than on the concave side of the retro-curvature, while the differentiation programs of the outer sheath, the inner sheath and, to a certain extent, the stalk (in particular the cuticle) start earlier on the concave than on the convex side.³² 

Melanocytes are oval or spindle-shaped dendritic cells, located at the apex on the dermal papilla, just below the precortical keratinocytes. The dendrites of the melanocytes insert between the cortical and medullary keratinocytes. Each melanocyte is connected to five keratinocytes to form the pigmentation unit. The dynamic process of hair pigmentation consists of three stages: the melanogenesis, the transfer of melanin granules to keratinocytes, and finally the formation of the pigmented hair shaft. Melanogenesis is characterized by a series of reactions, catalyzed by different enzymes, which result in the transformation of tyrosine into melanin pigments (Figure 1.3). This pigment production takes place during the anagen phase, under the control of neighboring cells, such as keratinocytes, fibroblasts and endothelial cells, which act by paracrine or autocrine mechanisms and can be modified by hormonal signals. This complex metabolism includes a common pathway, characterized by the conversion of l-tyrosine to l-DOPA (3,4-dihydroxyphenylalanine) and then of l-DOPA to DOPAquinone under the action of tyrosinase (TYR). The common pathway diverges at this stage. In the absence of cysteine, dopachrome is spontaneously and gradually converted to 5,6-dihydroxyindole (DHI) by decarboxylic rearrangement. This conversion can be accelerated by the tyrosinase-related protein-2 (TYRP2) (also called dopachrome tautomerase (DCT)), which catalyzes tautomerisation to 5,6-dihydroxyindole-2-carboxylic acid (DHICA). Polymerization of DHI and DHICA results in eumelanins. The role of TYR and TYRP1 (tyrosinase-related protein-1) in this last step is confirmed in mice but not yet in humans. The DHI eumelanins are responsible for the black or brown coloring, the DHICA eumelanins for the light brown coloring. In the presence of cysteine, dopaquinone is spontaneously oxidized to cysteinylDOPA to give 5-S- and 2-S-cysteinyldopa isomers with a 5 : 1 ratio. Oxidation of these cysteinyl dopa isomers leads to the production of the reddish-brown pigment pheomelanin through the intermediate compound 1,4-benzothiazinyl-alanine. Pheomelanins are responsible for the blond reddish coloring. These eu- and pheomelanins exist in reduced or oxidized form. In general, both pathways coexist and the hair colour is determined by the ratio eumelanin/pheomelanin which is genetically controlled.^31,33–38 

Melanosomes contain fibrillar or lamellar material with a characteristic periodicity. Mature melanosomes undergo a bidirectional migration from the perinuclear region to the tips of the dendrites. This intracellular movement involves microtubules and various proteins. At the extremity of the dendrites, the melanosomes are transferred to the keratinocytes according to a mechanism that is still not well understood. Several hypotheses have been formulated: cytophagocytosis, release of melanosomes into the intercellular space followed by keratinocytes endocytosis keratinocytes, transfer of melanosomes by direct communication between the two cell types, process of cytophagocytosis of the dendritic ends by keratinocytes. The pigmentation unit is destroyed at the end of the anagen phase. During the neomorphogenesis, a contingent of dormant and inactive melanocytes located in the bulge is recruited to restock the bulb of the new follicle.^31,36 

The different stages of melanin production, distribution, and degradation depend on endogenous, genetic, and hormonal factors, as well as on exogenous factors such as the stimulation of photoprotection by UV.¹  During ageing, the first phenomenon is a decrease in tyrosinase activity. The migration of melasonomes will also be affected, as will the interactions between keratinocytes and melanocytes. This phenomenon, genetically programmed, may be accelerated by stress, smoking, or pathologies such as anaemia.³⁹ 

The follicle is associated to sweat and sebaceous glands, as well as to the arrector muscle, to form the pilosebaceous unit. Sebaceous glands are present on the entire surface of the body except the palms, soles, and dorsum of the foot. They are multilobed glands which end at the isthmus via their excretory canal. They are composed of several cell layers, from the periphery to the core: the basal membrane, the germinal layer, and then several sheets of undifferentiated cells, which express markers characteristic of stem cells and will give rise to the sebocytes. During this maturation period, which lasts about two weeks, the enzymatic equipment necessary for lipid synthesis is developed. The sebocytes then move to the core of the lobule and release the sebum into the infundibulum via the excretory duct. Sebum has a very complex composition. The “native” sebum, secreted by the sebocytes, is essentially composed of triglycerides (57%), mono- and diesters (26%), and squalene (12%). It is modified during transit in the infundibulum by the addition of lipids of epidermal origin such as sterols, sterol esters, and ceramides. The “final” sebum, excreted at the surface of the scalp, contributes to the formation of the surface hydrolipidic film which lubricates the hair and protects the epidermis.^40,41 

Eccrine sweat glands are widely distributed on the skin and scalp, with 2–5 billion in humans. These glands abut directly on the surface of the epidermis, unlike the apocrine sweat glands which are attached to the pilosebaceous follicles in the axillary, inguinal, and intergluteal folds. The eccrine sweat glands consist of a sweat glomerulus, a hairy acinus that produces sweat, located in the dermis or at the dermal-hypodermal junction, and which extends into the sweat duct that evacuates the sweat to the epidermis. The glomerulus itself comprises a secretory and an excretory part. The primitive sweat, produced by the secretory cells of the glomerulus, is isotonic to plasma. It is progressively modified by resorption phenomena in the excretory duct.^41,42 

The arrector muscle is a smooth muscle stretched between the dermal-epidermal region and the sub-isthmic region of the hair. Its contraction causes the hair to straighten, called horripilation.^1,2 

The cutaneous vascularization is ensured by arterioles that ascend into the dermis, forming a plexus that supplies the cutaneous structures and in particular the hair follicle. These arterioles are particularly concentrated in the lower part of the hair follicle and form a rich anastomotic network connected by cross shunts in contact with the papilla. A second capillary network is located in the sebaceous gland. It extends to the surface of the skin. These two networks are connected by a parallel system of larger vessels that descend along the sides of the follicle. The profound network, in contact with the papilla, is very developed during the anagen phase and involutes during the catagen and telogen phases, whereas the superficial networks do not show any modification.^1,2  These results are supported by a study by Ford et al., which shows by the volumetric multispectral optoacoustic tomography method that the dermal papilla in the anagen phase has a high perfusion rate with an oxyhaemoglobin saturation of about 99%.⁴³  The venous circulation is parallel to the arterial circulation. Finally, each papilla has its own lymphatic system.

The nerves that supply the hair follicles are organized in the same way as the dermal nerve network and include sensory afferents and autonomic sympathetic nerves. They emerge in the dermis and ascend to innervate the hair follicle from the bulb to the epidermis. At the level of the sebaceous gland, a collar of nerves overlies certain follicles. Fibers may extend from this collar to innervate local structures or form a second dermal plexus. Nerve endings extend from this network to innervate the papillary dermis and the epidermis. ^1,2 

The hair cycle consists of three phases: a growth (anagen) phase, a regression (catagen) phase, and a resting (telogen) phase (Figure 1.4). These phases are regulated by a very complex system involving cytokines, hormones, neurotransmitters, transcription factors, and enzymes. At each stage, the hair follicle epithelium, but also the mesenchyme, the extracellular matrix, and the vessels undergo dramatic changes.² 

The anagen phase concerns about 80–90% of the hair mass and lasts two to three years in men and six to eight years in women; the growth rate, genetically determined, is about 0.22–0.52 mm per day or 0.6–1.4 cm per month. During this phase, the new hair appears in the hair follicle and grows through a mechanism of massive division of the cells above and around the dermal papilla. In fact, this process concerns all the epithelial compartment, with the highest activity observed in matrix cells.²  The signal that triggers this division is emitted when the cells of the dermal papilla of the previous hair are in the telogen phase, which gradually rises to the surface and comes into contact with the stem cells of the bulge. Unlike epithelial progenitor cells, bulge cells are pluripotent and indefinitely divisible, and form a reservoir from which, at each telogen/anagen transition, a subpopulation is recruited to repopulate the bulge of the newly formed follicle and regenerate a pigmentation unit, while another subpopulation will remain in the bulge.^23,44 

The anagen phase can be divided into six stages (I–VI). During stages I to V (so-called proanagen stages), hair progenitor cells multiply very quickly and form an invagination that extends into the epidermis, in which all the components of a new follicle organize and differentiate. Some keratinocytes spread to the periphery of the hair follicle to form the outer and inner epithelial sheaths; others extend to form the hair shaft. They accumulate keratin and melanosomes. This is among the most intense and rapid mitotic activities in the body. This stage is controlled by several signaling pathways (BMP, EGF, EGF, and NOTCH, in particular) as well as by transcription factors, and is accompanied by a massive angiogenesis. Lymphatic vessels in the bulge could also be involved. During anagen VI (metanagen stage), the new hair fiber is produced, and the new hair shaft appears on the skin surface.^{10,28,30,45–48} 

Towards the end of the anagen phase, keratinocytes stop proliferating. Melanocyte dendrites retract, TYR and TYRP2 activity collapses, and the lower two-thirds of the hair follicle rapidly regress.^10,20  At the same time, blood vessels involute, growth factor production decreases, and epithelial cells of the lower telogen follicle no longer show significant DNA or RNA synthesis.⁴⁹  These different compartments actually undergo a process of terminal dedifferentiation and programmed apoptosis that leads to the rapid involution of the lower part of the follicle, while preserving a cluster of dermal fibroblasts that corresponds to the remnants of the dermal papilla. This short transition period of 2–4 weeks corresponds to the catagen phase.^2,10 

The follicle finally enters the telogen phase, which lasts about two to seven months and affects 10–20% of the hair mass. The hair follicle regresses to about half its original size.^2,10  A thin layer of epithelial cells covers a cluster of dermal fibroblasts which corresponds to the remains of the dermal papilla. At this stage, this is positioned directly under the bulge, which allows direct interactions between the bulge stem cells and the dermal papilla. Keratin synthesis is also stopped, with the exception of keratin 14 which continues in the epithelial sac to which the hair fiber is anchored. When the lower part of the follicle is completely detached from the papilla, the “club hair” is formed. The telogen hair shaft can be retained for months in this epithelial sac. Factors such as health status, nutritional status or season can influence the growth and duration of the telogen phase.^2,10 

Recently, the concept of an exogenous phase has emerged.⁵⁰  This phase corresponds to the period during which the process of release of the hair shaft is initiated and successfully executed. The exogen phase ends when the shaft is liberated. This hypothesis is based on the observation that a hair shaft plucked in the telogen phase shows major morphological differences with the root of a shed hair shaft. Whereas the telogen root still has compact nucleated cells surrounding a cornified nucleus, the shed hair root has very few cells separated at their outer edge by an intercellular cleavage. The assumption that newly anagenic hair regrows resting hair is challenged by the hypothesis of a highly controlled active process. Finally, the existence of an interval between exogen hair extrusion and emergence of new anagen hair, during which the follicle remains empty, the so called kenogen phase, has been recently identified.^2,51 

The hair follicle presents three distinct origins: the infundibulum, isthmus, bulge, bulb, and keratinocytes are of ectodermal origin, the papilla is of mesodermal origin, and the melanocytes are of neuroectodermal origin.^52,53 

Hair development requires close collaboration between these structures during embryogenesis via growth factors, cytokines, neuropeptides, neurotransmitters, and hormones.¹⁰  Three phases, induction, organogenesis, and cytodifferentiation, in turn subdivided into eight morphologically distinct stages, have been identified (Figure 1.4).^10,52–54  The induction phase begins around the eighth week of development and includes stage 0 and stage 1. Stage 0 is marked by the appearance of an interacting gradient of reciprocal interactions between the surface ectoderm, a superficial sheet that covers the entire body of the embryo, and the underlying mesoderm, thus creating an inductive field in the epidermis. In stage 1, the surface ectoderm gives rise to keratinocytes and the epithelial resulting structures: hair, sweat, and sebaceous glands. Some keratinocytes enlarge and elongate to form the ectodermal placodes.^10,47,54  These placodes will expand and form epithelial ingrowths that invaginate obliquely into the adjacent dermis, with the degree of angle determined by the location of the hair follicle. Unlike other mammals, the final number of follicles (between two and five million follicles, of which 100 000 to 150 000 are located on the scalp) is acquired at this stage. Placode formation subsequently expands in a wave caudally and ventrally over the skin of the fetus. The message initiating this phenomenon originates from a cluster of fibroblasts located in the underlying dermis, and the dialogue between these signaling pathways promotes the reciprocal proliferation of the ectoderm and mesoderm.^10,54  These include the growth factor TGF-β, bone morphogenetic protein (BMP) type 4, and lymphoid enhancer binding factor (LEF-1). Precise localization and growth of placodes is determined by signaling pathways including in particular the wingless protein (Wnt)/β-catenin for the hair follicle morphogenesis; in parallel, other signaling pathways inhibit placode fate in surrounding cells.^4,10,28 

The organogenesis phase, which corresponds to stages 2 to 5, begins around the sixteenth week. Stage 2 (the so-called germ stage) is marked by massive proliferation of germ cells of the ectoderm, leading to the formation of the dermal papilla. The resulting structure is called the hair germ. This phenomenon again requires an inductive interaction with the underlying mesoderm, which itself sends specific signals to the ectoderm cells, thus forming a reciprocal signaling pathway.^4,10  During stages 3 to 5, collectively known as the peg stage, the proximal keratinocytes continue to proliferate and surround the papilla. During stage 5, the keratinocytes form the inner root sheath, a process that will initiate terminal differentiation into the hair shaft.^4,10,28 

The cytodifferentiation phase, which begins between the eighteenth and twentieth week, corresponds to stages 6 to 8 of development. The lower end of the germ enlarges to form the bulb, which will rapidly deepen under the thrust of the papilla. The inner sheath completes its differentiation by forming a rigid structure in which the keratinocytes differentiate to form the hair shaft. At the same time the cylindrical layers of the outer sheath appear around the inner sheath. Other keratinocytes, located in the distal part of the follicle, will differentiate into sebocytes and apocrine gland precursors. Vasculo-nervous structures also appear at this stage. The sebaceous precursor develops in the obtuse angle formed by the epidermis and the future hair follicle. The first cells metabolize glycogen and secrete lipids. It becomes functional between the thirteenth and sixteenth week of life and secretes the vernix caseosa.⁵⁵ 

Melanocytes are derived from undifferentiated, unpigmented cells, the melanoblasts, originating mainly from the neural crest cells, a transient population of cells arising from the dorsal part of the neural tube. Migration is modulated by the surrounding environment, consisting of environmental factors, extracellular matrices (ECM) and direct interactions with neighbouring cells encountered on their path. It begins early, between the sixth and seventh week of development, and reach the mesoderm, the ectoderm and the hair follicles between the eighth and fourteenth week. Some melanoblasts will proliferate and then differentiate into epidermal melanocytes, while others, called transit-amplification melanoblasts, leave the epidermis to distribute into the developing hair follicles as dopa-positive and dopa-negative cells.^31,33,56  At around E15.5, these melanoblasts concentrate near the placodes. They will then colonize the follicle in two distinct locations. A first contingent will colonize the bulge, where they form the melanocytic stem cell population, and serve as a reservoir with the hair follicle stem cells, responsible for the cyclic regeneration of hair follicle epithelial cells. A second contingent will colonize the hair bulb above the dermal papilla, where it will differentiate and proliferate to produce melanosomes. These melanoblasts will be incorporated into the first follicle to form the pigmentary unit at the apex of the dermal papilla. The first melanosomes will be produced around the twenty fourth week, and the first melanocyte dendrites around the twenty eighth week, at which time the first melanosomes will be incorporated into the keratinocytes. The bulge, for its part, is derived from a contingent of neural crest stem cells with a unique gene expression profile that differentiates them from embryonic neural crest cells and epidermal stem cells.^26,31,33,57 

The first hair emerges on the scalp around the sixteenth or seventeenth week of pregnancy. At the twentieth week, the scalp is entirely covered. From the twenty third week onwards, the hair has an oblique trajectory in relation to the skin, whose angle is determined by the degree of tension of the ectoderm caused by the concurrent development and maturation of the underlying brain. These first waves are made up of very fine (less than 30 µm in diameter), soft, short (about 2 mm long), non-pigmented and non-medullated hairs, which form the lanugo, visible in preterm neonates.

A second cycle of growth then occurs to form the downy or vellus hair, which is fine (diameter between 5 and 30 µm), short and poorly pigmented. The vellus hair penetrates the reticular dermis but not the subcutaneous fat layer. It is visible in the full-term neonate and continues to grow throughout life.^2,46,58  It should be noted that a significant proportion of hair remains in the vellus stage throughout life, even on the scalp, where it may represent up to 7–25% of the hair present. The intermediate hair is seen after birth on the scalp. It has a diameter of between 30 and 60 µm, a cuticle, sparse pigmentation and a fragmented (or absent) medulla. The intermediate hair will gradually develop into a pigmented terminal hair. This has a larger cross-section (>60 µm) as well as medulla, and penetrates deep into the underlying dermis, with a bulb embedded in the subcutaneous fat.^2,46  Its size and shape vary according to location and potential function. Initially, only the hairs on the eyebrows, eyelashes and scalp develop into terminal hairs. Progressively, depending on age, sex, and anatomical region, the transformation to terminal hair continues. At puberty, hair in certain areas of the body is replaced by longer, thicker, pigmented adult hair. This begins in the pubic and axillary areas in both sexes and continues with the eyelashes and eyebrows. Male facial hair begins to appear about two years after the onset of pubic hair growth.²  The transformation of vellus hair to intermediate and then terminal hair is androgen dependent, as are the transformations observed at puberty in both sexes.^2,59,60  Growth hormone is also required for a full androgenic action.⁶¹ 

At the end of fetal life and the beginning of the neonatal period, all follicles are synchronized in the same phase of the cycle. A few weeks after birth, the follicles regress in two successive waves, starting in the frontal area and progressing towards the occipital area. As telogen hair predominates in the occipital area, hair loss often produces an area of temporary alopecia. Only a small area of hair above the occiput does not regress at this stage. The vellus hair shows a slow and synchronized growth. In subsequent cycles, intermediate hairs appear and show asynchronous cycles with a mosaic pattern. There is great inter-individual variability in the occurrence of this phenomenon. However, it is considered that between the twelfth and sixteenth month, the scalp is covered with terminal mosaic hairs.^2,58–60 

The rate of growth varies during the first months of life. During prepuberty, hair growth is most rapid at the vertex, whereas it slows down after puberty in both sexes compared to the growth rate measured at the occiput. The growth rate of terminal hair at the vertex and occiput is then relatively stable in adulthood, at about 0.35 mm per day. These regions present the more consistent linear growth rate compared to the other regions of the scalp.^61,62  Some variables may affect the growth rate, including seasons, pregnancy, and hormones.^2,46,63,64  To simplify the interpretation of hair concentrations, it is agreed that the average linear growth rate of human hair in the posterior vertex and occipital region is about 1 cm per month.^61,65,66 

As presented in this chapter, hair is a complex organ in constant interaction with its surrounding environment. During the first months of life, its anatomy and growth pattern diverge significantly from those of adult hair. The mechanisms of xenobiotic incorporation are closely related to hair cycling and melanogenesis, and the interpretation of the concentrations, often complex, must take into account these aspects.