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After formation of the lanugo hair that is characteristic of the prenatal period, there are two major types of hair classified according to size (Table 86-1). Terminal hairs are typically greater than 60 μm in diameter, possess a central medulla, and can grow to well over 100 cm in length. The duration of the growing stage (anagen) determines the length of the hair. The hair bulb of terminal hairs in anagen is located in the subcutaneous fat. In contrast, vellus hairs are typically less than 30 μm in diameter, do not possess a medulla, and are less than 2 cm in length. The hair bulb of vellus hairs in anagen is located in the reticular dermis. Terminal hairs are found on the scalp, eyebrows, and eyelashes at birth. Vellus hairs are found elsewhere, and, at puberty, vellus hair follicles in the genitalia, axillae, trunk, and beard area in men transform into terminal hair follicles under the influence of sex hormones. Terminal hair follicles in the scalp convert to vellus-like or miniaturized hair follicles during androgenetic alopecia (see Chapter 88).1,69
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The curvature of the hair varies greatly among different individuals and races, and ranges from straight to tightly curled. Curved hair shafts arise from curved hair follicles. The shape of the inner root sheath is thought to determine the shape of the hair. Curled hair in cross section is more elliptical or flattened in comparison with straight hair, which is more round. Several genes influencing hair shape have been identified. Mutations in the epidermal growth factor receptor (EGFR) pathway and in insulin-like growth factor binding protein 5 result in curly hair in mice.70,71
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The upper follicle consists of the infundibulum and the isthmus, and the lower follicle consists of the suprabulbar and the bulbar areas (Fig. 86-2).14,66 The upper follicle is permanent, but the lower follicle regenerates with each hair follicle cycle. The major compartments of the hair from outermost to innermost include the connective tissue sheath, the outer root sheath, the inner root sheath, the cuticle, the hair shaft cortex, and the hair shaft medulla, each characterized by distinct expression of the hair follicle-specific keratins (Table 86-2).72,73
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The outer root sheath is continuous with the epidermis (see Fig. 86-2) at the infundibulum and continues down to the bulb. The cells of the outer root sheath change considerably throughout the follicle. The outer root sheath in the infundibulum resembles epidermis and forms a granular layer during its keratinization. In the isthmus, the outer root sheath cells keratinize in a trichilemmal fashion, lacking a granular layer. Trichilemmal keratinization occurs where the inner root sheath begins to slough. Desmoglein expression markedly changes here as well and trichilemmal or pilar cysts retain these characteristics.74 Keratinocytes in the outer root sheath form the bulge at the base of the isthmus (see Section “Hair Follicle Stem Cells”). These cells generally possess a higher nuclear to cytoplasmic ratio compared with other areas of the follicle. Moving downward, the outer root sheath cells become much larger and contain abundant glycogen in the suprabulbar follicle. In the bulb, the outer root sheath consists of only a single, flattened cell layer that can be traced to the base of the follicle.
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The inner root sheath extends from the base of the bulb to the isthmus and contains four parts from outermost to innermost: companion layer, Henle layer, Huxley layer, and the inner root sheath cuticle. The companion layer (see Fig. 86-2) has been referred to as the innermost layer of the outer root sheath, but recent evidence indicates that it is more like inner root sheath than outer root sheath.75 The companion layer attaches to Henle layer and moves upward with the rest of the inner root sheath; thus, it provides a slippage plane between the outer root sheath, which is stationary, and the inner root sheath.76 The companion layer is prominent in some follicles (e.g., the beard) compared with others. The cells of the companion layer are flat compared to the cuboidal outer root sheath cells and express a type II cytokeratin, K6hf.75 Henle layer is one-cell-layer thick and is the first to develop keratohyalin granules and the first to keratinize. Huxley layer is two to four cell layers thick and keratinizes above Henle layer at the region known as Adamson fringe. Some cells within Huxley's layer protrude through Henle layer and attach directly to the companion layer. These cells are called Fluegelzellen or wing cells.77 The cells of the inner root sheath cuticle partially overlap, forming a “shingled roof” appearance, and they intertwine precisely with the cuticle cells of the hair shaft. This association between the two cuticles anchors the hair shaft tightly to the follicle. The inner root sheath, composed of hard keratins and associated proteins (see Table 86-2), is thought to dictate hair shape by funneling the hair shaft cells as they are produced. The transcription factor, GATA-3, is critical for inner root sheath differentiation and lineage. Mice lacking this gene fail to form an inner root sheath.54
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The hair shaft (and inner root sheath) arises from rapidly proliferating matrix keratinocytes in the bulb, which have one of the highest rates of proliferation in the body. The cells of the future hair shaft are positioned at the apex of the dermal papilla and form the medulla, cortex, and hair shaft cuticle (see Fig. 86-2). Immediately above the matrix cells, hair shaft cells begin to express specific hair shaft keratins in the prekeratogenous zone. The differentiation of hair shaft cells in this zone is dependent on the Lef-1 transcription factor. Lef-1 binding sites are present in most hair keratin genes. BMP receptor type 1a is also critical for matrix cell differentiation into the hair shaft, because loss of this receptor prevents hair shaft differentiation.61–63
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The hair shaft cuticle covers the hair, and its integrity and properties greatly impact the appearance of the hair. Once the hair exits the scalp, the cuticle endures weathering, and it is often completely lost at the distal ends of long hairs. Inside the cuticle, the cortex comprises the bulk of the shaft and contains melanin. The cortex is arranged in large cable-like structures called macrofibrils. These, in turn, possess microfibrils that are composed of intermediate filaments. The medulla sits at the center of larger hairs, and specific keratins expressed in this layer of cells (see Table 86-2) are under the control of androgens.78
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The dermal papilla (see Fig. 86-1) is a core of mesenchymally derived tissue enveloped by the matrix epithelium. It is comprised of fibroblasts, collagen bundles, a mucopolysaccharide-rich stroma, nerve fibers, and a single capillary loop. It is continuous with the perifollicular sheath (dermal sheath) of connective tissue that envelops the lower follicle.
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Tissue recombination experiments have shown that the dermal papilla has powerful inductive properties, including the ability to induce hair follicle formation when transplanted below nonhair-bearing footpad epidermis.76,79 This shows that the tissue patterning established during the fetal period can be altered under appropriate conditions. In human follicle, the volume of the dermal papilla correlates with the number of matrix cells and the resulting size of the hair shaft.80 In mice, sizes of the hair bulb and hair diameter strongly depend of the proliferative activity of the matrix keratinocytes.81
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Many soluble growth factors that appear to act in a paracrine manner on the overlying epithelial matrix cells originate from the dermal papilla. Specifically, keratinocyte growth factor (KGF) is produced by the anagen dermal papilla, and its receptor, FGF receptor 2 (FGFR2), is found predominantly in the matrix keratinocytes. Injections of KGF into nude mice produce striking hair growth at the site of injection,82 suggesting that KGF is perhaps necessary for hair growth and cycling. However, surprisingly, KGF knockout mice develop morphologically normal hair follicles that produce “rough” or “greasy” hair; thus, KGF's effects on hair follicle morphogenesis and cycling appear dispensable or replaceable by other growth factors with redundant functions.83
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Hair Follicle Innervation
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Myelinated sensory nerve fibers run parallel to hair follicles, surrounding them and forming a network.84 Smaller nerve fibers form an outer circular layer, which is concentrated around the bulge of terminal follicles and the bulb of vellus follicles. Several different types of nerve endings, including free nerve endings, lanceolate nerve endings, Merkel cells, and pilo-Ruffini corpuscles are found around hair follicles.85 Each nerve ending detects different forces and stimuli. Free nerve endings transmit pain, lanceolate nerve endings detect acceleration, Merkel cells sense pressure, and pilo-Ruffini structures detect tension. Perifollicular nerves contain neuromediators and neuropeptides, such as substance P or calcitonin gene-related peptide, that influence follicular keratinocytes and alter hair follicle cycling.86–90 Conversely, hair follicle keratinocytes produce neurotrophic factors that influence perifollicular nerves and stimulate their remodeling in hair cycle-dependent manner.90,91 Merkel cells that are considered neuroendocrine cells also produce neurotrophic factors, cytokines, or other regulatory molecules. Because Merkel cells are concentrated in the bulge area, some have postulated that these secreted factors may influence the cycling of the hair follicle.92
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Perifollicular Sheath
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The perifollicular sheath envelops the epithelial components of the hair follicle and consists of an inner basement membrane called the hyaline or vitreous (glassy) membrane and an outer connective tissue sheath. The basement membrane of the follicle is continuous with the interfollicular basement membrane. It is most prominent around the outer root sheath at the bulb in anagen hairs. During catagen, the basement membrane thickens and then disintegrates.
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Surrounding the basement membrane is a connective tissue sheath comprised primarily of type III collagen. Around the upper follicle, there is a thin connective tissue sheath continuous with the surrounding papillary dermis and arranged longitudinally. Around the lower follicle, the connective tissue sheath is more prominent, with an inner layer of collagen fibers that encircle the follicle surrounded by a layer of longitudinally arranged collagen fibers.66
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When transplanted under the skin, this perifollicular connective tissue has the remarkable ability to form a new dermal papilla and induce new hair follicle formation.93 Even when the connective tissue sheath is transplanted to another individual, these follicles survive without evidence of immunologic rejection.