The hair cycle

Abstract

The hair coat, which keeps most mammals warm, dry and protected from harmful elements, requires a constant supply of new hairs throughout the lifetime of the animal. To produce new hairs, existing follicles undergo cycles of growth (anagen), regression (catagen) and rest (telogen). During each anagen phase, follicles produce an entire hair shaft from tip to root; during catagen and telogen, follicles reset and prepare their stem cells so that they can receive the signal to start the next growth phase and make the new hair shaft. The hair cycle represents a remarkable model for studies of the regulation of stem cell quiescence and activation, as well as transit-amplifying cell proliferation, cell-fate choice, differentiation and apoptosis in a regenerative adult epithelial tissue. Here we summarize the major events of the hair cycle, and touch on known regulators of the transitions. Detailed reviews of the hair cycle and its regulation can be found elsewhere (Lavker et al., 2003; Millar, 2002; Muller-Rover et al., 2001).FIG1In the embryo, the skin begins as a single layer of epidermal stem cells. Soon after, as mesenchymal cells populate the skin to form the underlying collagenous dermis, morphogenesis of the hair follicle begins (Schmidt-Ullrich and Paus, 2005). Specialized dermal cells organize in small clusters directly beneath the epidermal layer, stimulating the overlying epithelial stem cells to grow downward and produce a hair follicle. The follicle is contiguous with the epithelium; both are separated from the dermis by a basement membrane rich in extracellular matrix and growth factors synthesized and deposited largely but not solely by epithelial cells. As the follicle grows down, it assumes the shape of a rod several cell diameters wide. The inner layers begin to differentiate into concentric cylinders to form the central hair shaft (HS) and the surrounding channel, the inner root sheath (IRS). An inductive mesenchymal cluster called the dermal papilla (DP) becomes a permanent part of the follicle base (Jahoda et al., 1984; Kishimoto et al., 2000). It travels with the epithelial downgrowth and becomes enveloped by the hair bulb. The follicle becomes fully mature as its bulb nears the bottom of the dermis. At this point (in mouse back skin around postnatal day 6 or P6), the proliferative cells (matrix) at the follicle base continue to divide, producing progeny cells that terminally differentiate to form the growing hair that exits the skin surface.Histologically, anagen follicles are long and very straight, but the follicles are angled to permit the hair coat to lie flat along the body surface. The proliferating matrix cells have a cell-cycle length of approximately 18 hours (Lavker et al., 2003). Daughter cells move upwards, adopting one of six lineages of the IRS and HS; from outermost to innermost, the layers include Henley, Huxley and cuticle layers of the IRS, and the cuticle, cortex and medulla layers of the HS. As HS cells terminally differentiate, they extrude their organelles and become tightly packed with bundles of 10-nm filaments assembled from cysteine-rich hair keratins, which become physically cross-linked to give the hair shaft high tensile strength and flexibility. The IRS also keratinizes so that it can rigidly support and guide the hair shaft during its differentiation process, but its dead cells degenerate as they reach the upper follicle, thereby releasing the HS that continues through the skin surface. The duration of anagen determines the length of the hair and is dependent upon continued proliferation and differentiation of matrix cells at the follicle base.The matrix cells are referred to as transit-amplifying cells because they undergo a limited number of cell divisions before differentiating. As the supply of matrix cells declines, HS and IRS differentiation slow and the follicle enters a destructive phase called catagen. The timing of the first catagen onset varies slightly between strains of mice and varies significantly from one skin region to another. In pigmented mice, the progression of catagen is evident from the color of the skin, which changes from the dark gray to black of anagen to pale pink by telogen. As with morphogenesis, the first catagen begins in a wave, spreading from the top of the head caudally towards the tail and laterally down the sides of the animal. In back skin taken from the midline, the onset of the first catagen ranges from P14 at the upper back near the head to P18 in the lower back near the tail. Catagen lasts 3-4 days in mice.Some molecular regulators of the anagen-catagen transition have been identified, although how they work together to promote catagen or terminate anagen is not yet understood. Molecules that promote the transition to catagen include the growth factors FGF5 and EGF, neurotrophins such as BDNF and possibly the p75-neurotrophin receptor, p53 and TGFβ-family pathway members such as TGFβ1 and the BMPRIa (Andl et al., 2004;