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Hair follicle predetermination

¹ Department of Dermatology, Columbia University, College of Physicians and Surgeons, 630 W. 168th Street, Vanderbilt Clinic VC-1526, New York, NY 10032, USA
² Department of Biological Sciences, University of Durham, Durham DH1 3LE, UK
³ Department of Genetics and Development, Columbia University, College of Physicians and Surgeons, 630 W. 168th Street, Vanderbilt Clinic VC-1526, New York, NY 10032, USA

View larger version (46K): [in a new window]   Fig. 1. The hair cycle. In mammals, including humans, hairs do not persist but are periodically shed and re-grown in a ‘hair cycle’. Hair follicle (HF) cycling is associated with substantial structural reorganization of the HF itself – the complex epithelial sac that also contains a mesenchymal compartment (follicular papilla; FP) at its base. The HF consists of a permanent (upper) portion and a cycling lower portion that undergoes cycles of complete destruction and restoration. The stages of HF regression (catagen) and growth (anagen) are separated by the resting phase – telogen. The uppermost portion of the telogen follicle (the infundibulum) shares many structural and functional features with the interfollicular epidermis. Its lower margin is demarcated by the sebaceous gland duct. The attachment of the arrector pili muscle to the HF epithelium demarcates the bulge region, which is prominent in human (especially embryonic) HFs but is barely visible in the mouse. The induction of anagen is associated with a burst of proliferation in the lower portion of the telogen follicle. According to current views – in particular, the bulge activation hypothesis – the source of this proliferation is the HF stem cell population located in the bulge region (Cotsarelis et al., 1990). The nature of the anagen inductive signal and its source are still debated. With progression of early anagen proliferation, the HF grows downward and completely engulfs the FP, which also undergoes substantial structural changes. At this point, the prominent upward flow of epithelial cells is formed; these originate from the hair matrix, where active proliferation takes place. Proliferation of hair matrix cells results in the formation of the hair shaft (comprising three layers: medulla, cortex and hair cuticle) and inner root sheath (IRS; comprising three layers: cuticle, Huxley’s layer and Henle’s layer). The ascending HF layers are encased by the outer root sheath (ORS). The epithelial compartment of the anagen HF is surrounded by the dermal sheath, a structure of mesenchymal origin that is contiguous with the FP. The entire HF structure is encapsulated by a perifollicular connective tissue sheath. Anagen HFs (depending on their functional type) are associated with complex vascular and neural networks. Anagen lasts approximately two weeks in mice and up to 4-5 years in humans. With the transition to catagen, the lower HF portion undergoes apoptosis-driven diminution, and the hair bulb shrinks. The FP condenses and travels upward along with the regressing lower epithelial portion. It comes into direct contact the lower part of the overlying permanent portion of the HF. Interdigitation and specific patterns of keratinization of the hair shaft cells and cells of the ORS form the club hair, which anchors the hair shaft in the follicle.

View larger version (17K): [in a new window]   Fig. 2. Localization of putative stem cells of the bulge region (blue) and hair germ cells (red) in the mouse telogen hair follicle.

View larger version (29K): [in a new window]   Fig. 3. Comparison of cellular mechanisms that govern hair follicle progression through anagen as put forth by the bulge activation hypothesis and the hypothesis of hair follicle predetermination. (A) The bulge activation hypothesis states that the initial event of anagen is the direct activation of a bulge-localized stem cell population by follicular papilla signaling (yellow arrow). The resultant proliferation of bulge cells (black arrow) is the source of all hair follicle layers and of both the downward growth of the hair follicle and the upward growth of the hair shaft and inner root sheath (IRS). (B) The hypothesis of hair follicle predetermination proposes that anagen activation is a two-step process that includes the initial activation of hair germ cells (1) and consequent activation of bulge-localized cells (2). The activity of the hair germ cells results in the formation of the ascending hair follicle layers, including the IRS and hair shaft (white arrow), whereas proliferation of the bulge-localized cells produces the outer root sheath (black arrow).

View larger version (24K): [in a new window]   Fig. 4. Proposed cellular kinetics in the early anagen hair follicle. (A) In anagen I, the activation of hair germ cells (red) may be the initial event of anagen induction by a follicular-papilla-derived signal (yellow arrow). (B) In anagen II, the activity of the hair germ (yellow arrow) induces proliferation of putative stem cells of the bulge region (black arrows). (C) In anagen IIIa, the active downward growth of bulge-derived cells (black arrows) results in the formation of the outer root sheath and provides the penetration of the hair follicle into the deep dermis. (D) In anagen IIIb, the upward proliferation of hair germ cells (white arrows) results in formation of the ascending compartment of the anagen hair follicle (hair shaft and inner root sheath).

View larger version (26K): [in a new window]   Fig. 5. The stem cell hierarchy in the hair follicle (HF) and interfollicular epidermis. As previously suggested (Cotsarelis et al., 1990), the bulge region of the HF outer root sheath (ORS) harbors a population of stem cells (hatched blue). The proliferation of bulge-derived transient amplifying (TA) cells results in repopulation of the interfollicular epidermis and formation of the ORS (blue arrows), which both represent homogenous, terminally differentiating keratinocyte populations and share many common features. Under the influence of the neighboring mesenchyme (the follicular papilla in HF, and the underlying dermis in the interfollicular epidermis – red arrows), some cells of the bulge region progeny may reacquire their stem cell characteristics and form derivative stem cell populations (EPU progenitors in the interfollicular epidermis, and lateral disc cells in the HF – in blue).

View larger version (100K): [in a new window]   Fig. 6. The histology and immunohistochemistry of hairless (hr/hr) mouse skin. [Reproduced with permission (Panteleyev et al., 1998; Panteleyev et al., 1999a).] (A) The disintegration of HFs in hairless mouse skin results in physical separation of the follicular papilla (FP; alkaline-phosphatase-positive structures – arrows) and upper HF portions including utriculi (u), sebaceous glands (sg) and bulge cells. (B) The bulge-derived downward outgrowth in hairless mouse skin that recapitulates the outer root sheath (ORS) of the normal mouse HF. Bg, the bulge; bo, bulge outgrowth; apm, arrector pili muscle; dc, dermal cyst. (C) Immunohistochemistry (immunofluorescence) with mouse Ki-67-specific antibodies (red) reveals proliferating keratinocytes associated with the detached FP. (D) The cells of bulge-derived outgrowth are also Ki-67 positive (arrowhead), which suggests that they are also proliferating.

View larger version (31K): [in a new window]   Fig. 7. The formation of the lateral disc from the lowermost tip of the outer root sheath (ORS). (A) In the mouse hair follicle (HF), the ORS envelops the hair bulb asymmetrically, forming a leading edge at the front of its downward growth. This lowermost extension of the ORS forms a specific pathway for downward-migrating bulge-derived cells (white arrow). (B) 2D section of the mouse HF at the same stage of cycling (late anagen). Bulge-derived cells gradually concentrate in the lowermost portion of the ORS, forming the lateral disc. The pressure of the perifollicular connective tissue sheath should force the gradual submersion of the enlarging lateral disc (red arrow) into the hair matrix. (C) The human HF at a late anagen stage. The substantial thickness of the lower ORS portion may be sufficient to harbor a distinct cell population of bulge-derived cells (red arrow) and thus the formation of separate lateral disc may be not necessary.

View larger version (30K): [in a new window]   Fig. 8. Lateral disc transformations during anagen-catagen transition. (A) During anagen, bulge-derived cells that have high proliferative potential migrate downward (blue arrow) and form the lateral disc, which resides on the periphery of the hair bulb and is inactive. Hair matrix cells (red) actively proliferate. (B) In early catagen, owing to the diminution of the hair matrix, the lateral disc cells come into direct contact with follicular papilla (FP) cells. (C) In late catagen, lateral disc cells travel upward along with the FP and gradually transform into the hair germ (change of blue color into red). (D) In the telogen hair follicle (HF), hair germ cells and bulge cells reside as two separate and functionally discrete structures. Owing to FP-dependent ‘education’ during previous catagen, hair germ cells acquire selective sensitivity to FP-derived signaling and the commitment to produce the ascending HF layers.