In the early embryo, the skin begins as a single layer of ectodermal cells from which the epidermis and hair follicles are derived. In response to a mesenchymal cue, an ectodermal cell will choose to form a hair follicle rather than epidermis and begin to proliferate and grow downward. In response to a subsequent ectodermal message, the underlying mesenchymal cells organize and become the dermal papilla of the hair follicle. Finally, in response to a message from these dermal papilla cells, the developing hair follicle now grows and differentiates (for review see Hardy, 1992). the basement membrane that separates the epithelium together, these environmental factors can make the length of telogen highly variable. and mesenchyme. This draws the dermal papilla up to the base of the permanent epithelial portion of the follicle, a region known as the bulge. At this point, the follicle The Bulge: The Skin Epithelial Stem Cell Niche The ability of the epidermis, sebaceous gland, and hair enters a resting phase known as telogen. Telogen can last for months in humans or barely at all, as in the case follicle to constantly renew is a special feature of skin epithelium. Self-renewing tissues are able to do so by of rodent whisker follicles. The old hair shaft, left without anchorage, becomes fragile and can be liberated from virtue of a compartment of stem cells, which have the unique capacity to divide in a fashion such that some its site when physically stressed. Following this resting period, a new hair cycle is seem- of the daughter cells are stem cells, able to sustain the compartment of multipotent cells, while other progeny ingly spontaneously initiated, as a fresh hair germ-like structure streams down from the bulge (Figure 2). In are biologically distinct in some way from their parent stem cells (Figure 3; reviewed by Fuchs and Segre, 2000; collaboration with the dermal papilla, the hair germ now blossoms into a fresh new follicle, retracing many of the Watt and Hogan, 2000). It is not yet clear whether this heterogeneity arises from the ability of a stem cell to same morphological steps that occurred during embryogenesis. The mesenchymal-epithelial cross-talk divide asymmetrically or from an environmental asymmetry that exposes some daughter cells to different that led to the production of matrix cells, IRS, and hair during the early stages of embryonic morphogenesis external transducing signals. Despite its relatively small size, the bulge has been purported to be the residence appears to be similar to the initiation of anagen in the postnatal hair cycle. of the self-renewing stem cells of the skin (Cotsarelis et al., 1990; Taylor et al., 2000; Oshima et al., 2001). Cells Hair growth continues in this cyclic fashion throughout postnatal life. In rodents, the completion of the first two emanate from this compartment to regenerate the lower two-thirds of the hair follicle at the initiation of each new hair cycles is largely synchronous, although progressive asynchrony develops with subsequent cycles. This is cycle. This compartment also seems the likely source for the hair follicle cells that regenerate the epidermis likely attributable to the environmental impact on the telogen phase of the hair cycle. Plucking can shorten during wound healing (Potten and Morris, 1988). Like other stem cells, bulge cells are slow cycling, thedurationoftelogen, andmanyotherfactorsinfluence this phase, including the nutrients, steroids, neurotrans- and when labeled with a tracer nucleotide these cells will retain the label over extended chase periods (Bickmitters, cytokines, and growth factors that are either delivered by the vasculature surrounding each follicle enbach and Mackenzie, 1984; Morris and Potten, 1999 …