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The hair follicle is an outstanding model for dissecting the biology of vertebrate stem cells. This SnapShot illustrates the current understanding of key aspects of hair follicle stem cell development and homeostasis.
Hair follicle (HF) induction involves a series of inductive and repressive interactions within the early ectoderm. The HF epithelium proliferates and elongates, growing downward into the dermis/subcutis region. Once the HFs are fully developed, they cycle through catagen (regression), telogen (resting), and anagen (growth) stages, using their resident stem cells to fuel the new HF epithelium.
Hair follicle stem cells (HFSCs) arise within the early committed placode epithelium before the physical appearance of the bulge. These Sox9+ HFSCs localize to the suprabasal layer and are the earliest long-term label-retaining stem cells (red). Sox9 appears to specify the HFSC and bulge.
Lhx2 expression defines more transient progenitor cells in the basal layer of the hair placode. As the embryonic hair germ develops to the hair peg stage, Sox9+ HFSCs expand and localize to the upper portion of the HF epithelium, the upper outer root sheath (ORS), which later becomes the presumptive bulge. These long-term HFSCs contribute to embryonic HF growth as the Lhx2+ transient progenitors exhaust their proliferative capacity. Lhx2 expression diminishes in the lower hair peg but reappears in the Sox9+ cells. Together with NFATc1 and Tcf3, these four transcription factors define both the embryonic and adult HF bulge. Subsequent elongation and retraction of the HF over the hair cycle occurs in the cycling portion below the HFSC compartment.
The stem cell niche consists of heterogeneous pools of stem cells that differentially contribute to tissue regeneration. At the telogen stage, the HFSC niche consists of the bulge and secondary hair germ (hair germ or HG hereafter). The bulge is a structure between the sebaceous gland (SG) and arrector pili muscle and consists of K5/K14 epidermal cells continuous from the epidermis. The HG is a group of P-cadherin-positive epidermal cells extended from and located below the bulge; it is morphologically similar to the embryonic hair germ, hence the name. The bulge constitutes the quiescent niche and possesses DNA label-retaining stem cells. The HG receives dermal papilla signals first and becomes activated at the end of telogen. Bulge cell activation occurs later than HG activation. Both HG and bulge stem cells contribute to the next hair follicle epithelium and, with wounding, to the overlying epidermis. The specific markers for adult bulge are CD34 and K15, whereas Lgr5 is expressed in both the lower bulge and HG. In contrast to the slow-cycling nature of some bulge cells, LGR5+ stem cells are actively proliferating yet contribute to all HF lineages and are long-term stem cells. Unlike other bulge markers, Lgr5 is detected in the lower ORS during anagen; these stem cells recycle after each hair cycle and regenerate the bulge and HG. SG and epidermis are generated from other stem cells that reside in the HF, but not in the bulge and HG stem cells, although purified bulge/HG stem cells are multipotent and are able to generate HF, epidermis, and SG when transplanted. SG is generated from SG-specific Blimp1+ stem cells that localize to the epidermal cells at the junction between bulge and SG. Lgr6, MTS24, and Lrig1+ stem cells constitute partially overlapping stem cell niches located between the upper bulge edge and opening to the epidermis. Lgr6+ cells normally contribute long-term progenitors to the epidermis and SG in the absence of wounding.
HFSCs function within a complex and multidimensional microenvironment. HFSC gene expression profiles reveal potential crosstalk with neighboring niche cells. Shown in the panel are putative niche cells interacting with bulge/HG stem cells. Basement membrane and dermal sheath cells abut the bulge and HG stem cells. Sensory nerve fibers wrap around the upper bulge region, and blood vessels are a few cell diameters away from the HF. The dermis, subcutis, and perhaps the immune system exert influence over bulge/HG stem cell maintenance and activation. The signals emanating from some of these niche cells are starting to be identified. Primary interactions and function of HFSCs depend on the mesenchymally derived dermal papilla that provides growth and timing signals such as FGF7. Dermal papilla gene expression changes dynamically from early to late telogen, suggesting that dermal papilla may also provide inhibitory signals to stem cell activation during early telogen. The inner layer of bulge cells, the K6+ CD34– cells (shown in the “bulge reformation” panel), functions to suppress bulge stem cell activation. Neural input also regulates stem cell function. Gli1+ cells in the upper bulge cells possess long-term stem cell activity in the epidermis during wound healing. Gli1 expression in the upper bulge, and the activity of the cells during wound healing, depends on hedgehog ligand released from the adjacent sensory nerve fibers.
Whereas the microenvironment regulates the bulge stem cells, the bulge in turn provides a niche for melanocyte and skin-derived precursors/nestin+ stem cells. Bulge stem cells promote melanocyte stem cell commitment and activation. At anagen onset, HFSCs activate melanocyte stem cells via Wnt signaling, and subsequently the two stem cell types interact reciprocally for activation and differentiation. In addition, bulge stem cells deposit nephronectin to the basement membrane, forming a niche for the arrector pili muscle.
The stem cells operating in their microenvironment give rise to the seven concentric layers of a mature HF. The matrix is composed of actively proliferating progenitors that are nonlabel retaining. The seven layers arise from layer-restricted progenitors, which are determined by their specific location relative to the dermal papilla. The layer-specific differentiation programs take place as the committed cells move upwards.
Upon receiving hair growth signals, HFSCs activate, divide, expand, and later migrate within the ORS to generate the mature HF epithelium. These HFSC descendents from bulge and HG lose CD34 and K15 markers but are Lgr5+ in the lower ORS. Interestingly, the numbers of cell division of these HFSC descendents differ along the ORS. Using the Tet-Off K14-H2B-GFP pulse-chase label-retaining method, the activated HFSCs were shown to migrate down the ORS, with more cell divisions the further they traveled. At full anagen when HF has grown to its full length, the faster cycling cells are in the lower ORS, and they have lost H2B-GFP label (LRC–); cells in the mid ORS still retain some H2B-GFP label, thus are slower cycling (LRC+/−); cells in the upper ORS retained most label and thus are slowest cycling (LRC+). Some of these ORS cells survive the apoptosis process during catagen and generate the new bulge in the next telogen.
The new stem cell niche derives from label-retaining and nonlabel-retaining cells of the previous anagen phase. The slowest cycling cells (LRC+) appear to become bulge stem cells and the majority of HG stem cells, whereas the slower cycling cells (LRC+/−) make up ~10%–20% of HG stem cells. The fast cycling cells (LRC–) also recycle back to the bulge. They generate K6+ CD34– nonstem bulge cells at the inner layer of the bulge. All of these stem and nonstem cells are generated at the end of catagen, as demonstrated by their corresponding marker expression and morphology. These regenerated bulge and HG stem cells are stem cells for the next hair cycle. These findings showed that the bulge may not be absolutely required to maintain HFSC stemness and that HFSCs may possess intrinsic stemness factors. The nonstem K6+ CD34– bulge cells do not contribute to the next HF; instead, they express quiescent factors that suppress bulge stem cell activation.
Stem cell activation into anagen is a highly regulated event emerging from multiple positive and negative signals. BMP, NFAT, and FGF18 signaling provide strong inhibitory signals that keep the bulge and HG quiescent, whereas Wnt and FGF7 provide activation signals that overcome quiescence signals. A variety of ligands and secreted antagonists for each of these pathways derive from the local environment. Neighboring HFSC niches also secrete regulatory factors, allowing one hair to couple with neighboring hairs. The dermal papilla secretes BMP antagonists, Wnt antagonists, and FGF ligands that activate HG stem cells. These events lead to Wnt signaling activation and β-catenin stabilization in HG cells and thus activate HG stem cells to proliferate and initiate hair growth. How each factor contributes to the exquisite timing of hair follicle cycling remains poorly understood.