Hair Follicle Anatomy and Hair Cycle

Understanding hair follicle components and hair cycle is important to understanding the overall sensitivity and reaction of follicles to laser exposure. The hair follicle is a multicellular structure that generates an organ-specific product—a pigmented hair fiber, as a result of tightly coordinated interactions between epithelial, mesenchymal, and neuroectodermal cells of the follicle. The hair follicle can be divided into several anatomical compartments. The upper follicle is permanent, but the lower follicle regenerates with each hair follicle cycle. The infundibulum extends from the skin surface to the sebaceous duct. The isthmus is a middle portion, which extends from the duct of sebaceous gland to the exertion of arrector pilli muscle. The inferior segment or lower follicle part consists of the suprabulbar and the bulbar areas. The lower hair bulb comprises extensively proliferating keratinocytes and pigment – producing melanocytes of the hair matrix, whereas suprabulbar area contains differentiated cells derived from the hair matrix. The suprabulbar and bulbar areas are separated by a line across the widest part of the dermal papilla, and it is known as the Auber line. The dermal papilla is a cluster of mesenchymal cells. The extensive epithelial-mesenhymal interactions occurring in the hair bulb leads to the formation of the final hair follicle product—the hair shaft [17,18].

The hair follicle has a multilayered structure, where the major compartments include: the hair shaft, the inner root sheath, the companion layer, the outer root sheath, and the con­nective tissue sheath (Fig. 9.1). The hair shaft is subdivided into three layers: the medulla, cortex, and the cuticle. The major structural proteins of the cytoskeleton syn­thesized in the hair shaft are the keratins and keratin-associated proteins [19]. The medulla

Figure 9.1 Histomorphology of human anagen hair follicle. The major compartments are shown: (1) hair shaft, (2) inner root sheath, (3) outer root sheath, (4) connective tissue sheath. DP: dermal papilla.

is a central part of larger hair. Medullary cells of all types of male and female sexual hair constitutively express the Type I hair keratin hHa7, which is directly regulated by andro­gens [20]. The hair-shaft cortex is composed of longitudinally arranged fibers. The hair – shaft cuticle covers the hair, and its integrity and properties greatly impact the appearance and character of the hair. It is formed by a layer of scales, which interlock with opposing scales of the inner root sheath that allows the hair shaft and the inner root sheath to move upward in concert. The inner root sheath extends from the base of the bulb to the isthmus. It consists of four layers: companion layer, Henle’s layer, Huxley’s layer, and the inner root sheath cuticle. The cells of the inner root sheath cuticle partially overlap with the cuticle cells of the hair shaft, which also allows anchoring of the hair shaft to the base of the fol­licle. Inner root sheath cells express trichohyalin protein that is an intermediate-filament – associated protein, and play a role in the lateral aggregation, alignment, and stabilization of inner root sheath filament bundles [21]. The inner root sheath separates hair shaft from the outer root sheath, which forms the external concentric layer of epithelial cells in the hair follicle. The outer root sheath consists of several layers of cells. The thickness and cellular – ity of the outer root sheath vary with the level of the follicle: it is single-layered just about the bulb, the cell number is gradually increased in upward, and at the level of the sebaceous gland it becomes multilayered and is structurally similar to the epidermis [22]. The outer root sheath represents a heterogeneous cell population consisting of keratinocytes, stem cell progeny for keratinocytes, neuroendocrine Merkel cells, Langerhans cell, melanocytes precursors, and differentiating melanocytes [23,24].

One of the key components of the hair follicle is the dermal or follicular papilla. The papilla plays a critical role in regulating the hair follicle through various phases of hair cycle and is thought to be responsible for determining the character and pigmentation of the hair shaft. A stereologic study on 235 hair follicles from different sites suggested that the volume of the dermal papilla correlates with the number of matrix cells and the result­ing size of the hair shaft [25]. In contrast to the epithelial compartment of the hair follicle, the fibroblasts of the papilla have been reported to show no division, and be highly resistant to apoptosis.

Epithelial stem cells and daughter cells are located in the follicular bulge of the outer root sheath, and can be identify by long-term retaining of BrdU label or by immunodetec­tion of cytokeratins 15 and 19 [26,27]. Undifferentiated melanocytes, which are also located in a bulge area and the outer root sheath, can be visualized by immunostaining for tyrosine – related protein-2 [23].

Hair follicle has the unique property of undergoing cyclic changes of its structure and activity with periods of active hair fiber production (anagen), apoptosis-driven involution (catagen) and relative resting (telogen) phases [17,28]. The follicle regeneration is charac­terized by dramatic changes in its microanatomy and cellular activity. Cell fate during growth and involution is controlled by local balance of growth regulators that induce either proliferation/differentiation or apoptosis.

Proliferation, differentiation, and apoptosis in hair follicle keratinocytes are controlled by a number of signaling molecules, including the bone morphogenetic protein/ transforming growth factor-beta, epidermal growth factor, fibroblast growth factor, Hedgehog, insulin growth factor, Notch, neurotrophin, tumor necrosis factor, and Wnt families [17,18,28]. The decrease in proliferative activity or activation of apoptosis in the matrix region leads to a hair growth retardation and/or alterations in hair follicle cyclic activity.

In resting hair follicles, signaling exchange between the follicular epithelium and mes­enchyme appears to be minimal. Initiation of growth phase (anagen) in telogen hair follicle is accompanied by the activation of a large number of growth stimulatory signaling path­ways in both the hair follicle epithelium and mesenchyme. This leads to the activation of the keratinocyte and melanocytes stem cells located in the secondary hair germ, and the formation of hair bulb, in which keratinocytes extensively proliferate, the melanocytes make a pigment resulting in the formation of the hair shaft.

The anagen or growth phase of hair can be divided into six stages. During the early phases of anagen, hair progenitor cells proliferate, envelope growing dermal papilla, and begin to differentiate into the hair shaft and inner root sheath. In mid-anagen, melanocytes located in the hair matrix show pigment-producing activity, and newly formed hair shaft emerges and displaces the telogen hair. In late anagen, the formed hair bulb is located deep in the subcutaneous fat layer, and the new hair shaft emerges from the skin surface [29]. In addition to the hair follicle tissue remodeling, skin innervations and vascular networks also undergo substantial changes with the progression of anagen stage [30,31]. A modulation of angiogenesis in the skin can significantly affect the hair growth rate [32,33].

The hair follicle transformation from active growth to regression (anagen-catagen transi­tion) is characterized by a sudden decline in the dermal papilla secretion of growth factors for hair matrix keratinocytes, leading to the dramatic reduction of their proliferative activity, termination of hair-shaft production, and activation of massive apoptosis in the proximal hair follicle epithelium [28,34,35]. Morphologically and functionally, catagen is divided into eight substages [29]. During catagen, HF compartments involved in hair production are reduced in size that allows them to regenerate in the next hair cycle after receiving the appro­priate stimulation (Fig. 9.2). During catagen the dermal papilla is transformed into a cluster

of quiescent cells that moves from subcutis to the dermis/subcutis border to contact the dis­tal portion of the hair follicle epithelium which forms the secondary hair germ, containing follicular stem cells. The proximal part of the hair shaft contains a keratinized brush-like structure that is surrounded by epithelial cells of the outer root sheath. Anagen-catagen hair follicle transition may be triggered by a variety of stimuli, including signaling via death receptors, and by the withdrawal of growth factors that maintain cell proliferation and dif­ferentiation in the anagen hair follicle. The important roles for such growth factors as fibro­blast growth factor 5, insulin-like growth factor 1, transforming growth factor beta, neurotrophins, and PTHrp in catagen development have been demonstrated during the last decade [17,18,28,36,37]. Accumulating evidence suggests that apoptosis in every distinct hair follicle compartment is regulated differently. In addition, distinct cell populations in the hair follicle show a differential ability to undergo apoptosis. The majority of the follicular epithelial cells and melanocytes are highly susceptible to apoptosis, while dermal papilla fibroblasts and the populations of keratinocytes and melanocytes selected for survival dis­play a high resistance to apoptosis.

The duration of hair cycle stages varies in different body areas. Normal human scalp hair follicles have the longest anagen phase, which can last up to several years; they display a relatively short catagen phase (1-2 weeks) followed by the telogen phase lasting several months. The majority of the hair follicles on the scalp are in anagen phase (80-85%), whereas the remaining hair follicles (2%) are either in catagen or telogen phases (10-15%). Hair located on other body sites is characterized by longer telogen phases (up to 9 months). Anagen phase of the hair follicle of axilla, arms, legs, and thighs last only 3-4 months. The majority of the hair follicles in these areas are in the telogen phase (50-80%).