Hair Follicle Cycling and Signaling Molecules

 Hair growth is believed to be regulated by the interactive signals between the epithelial parts and mesenchymal-derived DP cells. Several cytokines, growth factors, hormones, neuropeptides and enzymes are involved in normal hair cycle control and may be involved in the pathogenesis of androgenetic alopecia (AGA). The specific molecular regulators modulated by androgens within hair follicles in the balding scalp are not fully understood.

Normally, mature hair has a regenerative cycling system that consists of three phases: anagen, catagen, and telogen. Anagen phase lasts 1–6 years on the human scalp with rapidly proliferating epithelial cells that finally differentiate into trichocytes and receive melanin granules from melanocyte cells, leading to the generation of a pigmented long HS. Following these active events, as the consequence of an undetermined hair cycle clock, epithelial and melanocyte cells undergo apoptotic processes, where a new HS replaces the old one in the next anagen phase. Catagen phase is the regression and distractive phase of the hair cycle that lasts only 4–6 weeks. Telogen phase follows this pre-programmed suicide where the remaining hair cells relax for 2–3 months on the scalp. Next, bulge epithelial stem cells undergo subsequent proliferation and differentiation in a new anagen phase. Therefore, the older HS is shed and replaced by a new HS. However, in some cases, a new HS is not generated, leading to hair loss.(10)

Hair is considered a complicated mini-organ within the skin, consisting of broad cell population diversity, ranging from epithelial to mesenchymal and neural crest cells. Communication between these cells results in generation, maintenance, and renewal of hair during development, cell cycle, and wound repair(10)

Multipotent epithelial cells are located in a specialized region called the bulge. In humans, the bulge region is considered a hair follicle (HF) stem cell niche located between the sebaceous gland and arrector pili muscle. Bulge epithelial stem cells can support not only growth of HFs and sebaceous glands but also provide all skin lineages to reconstitute new epidermis during wound repair. During the continual HF cycle, descendants of bulge epithelial stem cells contribute to the outer root and inner root sheath, as well as hair shaft (HS) (10).

Melanocyte stem cells are also located in the bulge niche. They are originated from neural crest cells and have the capacity to differentiate, produce melanin, and contact adjacent keratinocyte cells to distribute pigment granules along the skin and hair. Melanocyte stem cells cyclically proliferate and differentiate during hair cycle.(10)

In addition to the above-mentioned cells, other important hair niche components include cells with mesenchymal identities such as dermal papilla (DP) and dermal sheath cells (DSCs). These cells are located in the base of hair and surround the outer root sheath (ORS), respectively. DP cells (DPCs) regulate hair formation during embryogenesis and cell cycle during postnatal life. DPCs and DSCs are originated from mesoderm. Moreover, the neural crest origination of DPCs has been confirmed. Each HF is associated with a sebaceous gland that has its own stem cells, where its main cells, sebocytes, produce lipid-rich products. Other components of hair niche, including blood vessels, nerves, and adipocyte cells, surround the hair within the dermis to support hair growth and regeneration (10).

Although several studies have shown the importance of niche components and signals such as Wnt, bone morphogenetic proteins (BMPs), and sonic hedgehog (Shh) in regulating mouse HF behavior, the nature of human HF cells and their interaction with niche have not yet been fully understood (10).

The hair follicle is subject to constant turnover in the course of perpetual cycles through various stages of proliferation (anagen ), involution (catagen ), and resting (telogen ), with regeneration in the successive hair cycle. It is a major characteristic of anagen that not only the hair shaft is growing but that most epithelial hair follicle compartments undergo proliferation, with the hair matrix keratinocytes located around the dermal papilla showing the highest proliferative activity. Also, the newly formed hair shaft is pigmented by the follicle pigmentary unit (Paus and Cotsarelis, 1999). During the following catagen stage of the hair cycle, hair follicles enter a highly controlled process of involution that is characterized by a burst of programmed cell death (apoptosis) in the majority of follicular keratinocytes, termination of pigment production, substantial extracellular matrix-remodeling, and condensation of the dermal papilla (Paus and Cotsarelis, 1999).

The resulting shortening of the regressing epithelial strand is associated with an upward movement of the dermal papilla within the connective tissue sheath of the follicle. In telogen the hair shaft matures into a club hair, which is held tightly in the bulbous base of the follicular epithelium, before it is eventually shed from the follicle, usually as a result of combing or washing. It is still unresolved whether shedding of the telogen hair (teloptosis) is also an active, regulated process or represents a passive event that occurs at the onset of subsequent anagen, as the new hair grows in (Paus and Cotsarelis, 1999; Pierard-Franchimont and Pierard, 2001).

There are considerable variations in length of these stages depending on the body site location, with the duration of anagen determining the type of hair produced, particularly its length (Paus and Cotsarelis, 1999). On the scalp, hairs remain in anagen for a 2–7-year period of time, whereas that of telogen is 100 days, leading to a ratio of anagen to telogen hairs of approximately 9:1. On average the amount of new scalp hair formation essentially matches the amount that is lost due to shedding (approximately 100/day), thereby maintaining a consistent covering. Hair growth control: The controls that underlie the hair cycle reside within the hair follicle itself, and are believed to result from changes in the intra- and perifollicular expression of specific regulatory molecules and their receptors (Paus et al., 1999). Much circumstantial evidence suggests that the dermal papilla which is composed of specialized fibroblasts located at the base of the follicle, determines hair follicle growth characteristics, especially the regulation of cell proliferation and differentiation of hair follicle matrix: without papilla fibroblasts and an intimate contact with hair matrix keratinocytes anagen cannot be sustained.

Also, hair follicle morphogenesis can be induced by implanting dermal papilla cells under an appropriately receptive epithelium (Jahoda et al., 1984). Finally, it has been shown that implanting few cells of follicle dermal sheath tissue from the scalp from an adult human male is sufficient to form new dermal papillae and induce new hair follicles in the skin of a genetically unrelated female (Reynolds et al., 1999). There is substantial evidence from bioassays that cultured dermal papilla cells can secrete a number of cytokines, growth factors and other, yet unidentified bioactive molecules that influence growth in other dermal papilla cells, outer root sheath cells, keratinocytes, and endothelial cells (Stenn et al., 1996). Finally, the hair cycle is subjected to cycle modulation by numerous extrinsic influences, such as androgens (4)

Anrogenetic Alopecia (AGA) is characterized by progressive shortening of the duration of anagen with successive hair cycles, leading to decreased numbers of hair in anagen at any given time, and progressive follicular miniaturization with conversion of terminal to vellus-like follicles (Paus and Cotsarelis, 1999). The result is increased shedding of short-lived telogen hairs (telogen effluvium), while the affected hair follicles produce shorter, finer hairs that cover the scalp poorly. Since AGA involves a process of premature termination of anagen associated with premature entry into catagen, it is critically important to dissect the molecular controls of the anagen– catagen transformation of the hair cycle (Paus, 1996). Catagen has been suggested to occur as a consequence of decreased expression of anagen maintaining factors, such as insulin-like growth factor 1 (IGF-1), basic fibroblast growth factor (bFGF), and vascular endothelial growth factor (VEGF), and increased expression of cytokines promoting apoptosis, such as transforming growth factor beta 1 (TGFb 1), interleukin-1alpha (IL-1a), and tumor necrosis factor alpha (TNFa). Responses to androgens are obviously also intrinsic to the individual hair follicle: not only

does the response vary from stimulation to inhibition of hair growth depending on the body site, but androgen sensitivity also varies within individual areas, i.e. regression in AGA occurs in a patterned, progressive manner. Since many extrinsic hair growth-modulatory factors, such as androgens (Randall et al., 1992), apparently operate at least in part via the dermal papilla, research is currently also focused on identifying androgen-regulated factors deriving from dermal papilla cells. Of the several factors that have been suggested to play a role in hair growth, so far only insulin-like growth factor (IGF-1) has been reported as altered in vitro by androgens (Itami et al., 1995), and stem cell factor (SCF) has been found to be produced in higher amounts by androgen-dependent beard cells than in control non-balding scalp cells, presumably also in response to androgens (Hibberts et al., 1996). Since SCF is the ligand for the cell surface receptor c-kit on melanocytes, this may also play a role for hair pigmentation.

The free radical nitric oxide, generated by different types of epidermal and dermal cells, has been identified as an important mediator in various physiological and pathophysiological processes of the skin, such as regulation of blood flow, melanogenesis, wound healing, and hyperproliferative skin diseases. This biomolecule is apparently formed by the endothelial isoform of nitric oxide synthase, which was detected at the mRNA and protein levels. Remarkably, basal NO level was enhanced threefold by stimulating dermal papilla cells with 5α-dihydrotestosterone (DHT) but not with testosterone. NO is a signaling molecule in human dermal papilla cells and implicate basal and androgen-mediated NO production to be involved in the regulation of hair follicle activity.(11)


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