**2. Hair follicle: structure, cycling and stem cells**

HF is a skin appendage with very complex structure undergoing lifelong periods of morphogenesis. The major part of HF is produced by the epithelium. Highly proliferative matrix cells in HF bulb gradually move upwards in the course of differentiation. They are progenitors for the inner and outer root sheaths and hair shaft later on. Mesenchymal portion of HF includes dermal papilla (DP) and HF connective tissue sheath. DP is located inside the bulb and is separated from the matrix cells by a basement membrane. In a lower part of the bulb, DP contacts with the dermal sheath that surrounds the entire follicle. This structure is maintained throughout the hair-growth phase – anagen. With time, when HF transits into the destructive phase–catagen–the lower two-thirds of the HF epithelial strand degenerate and the hair shaft production stops. DP also becomes smaller but its losses are much less significant and are mainly caused by reduced content of an extracellular matrix [5] and migration of cells between the DP and the adjacent dermal sheath [6]. During catagen, HF is reduced to a tiny epidermal strand surrounded by a basement membrane. As it retracts, the DP is pulled upward to the upper permanent portion of the HF containing bulge stem cells [7].

Then HF enters the resting phase – telogen. The transition from telogen to anagen is the beginning of a new HF cycle, a process that continues throughout life. In mice, the lengths of anagen and catagen phases are similar from one cycle to the next, while each telogen becomes longer than the previous one. This results in progressive asynchrony in HF cycling with age [8].

Now it is quite clear that the regeneration cycle is maintained by activity of HF stem cells. HF is considered to be a valuable source of adult stem cells (SCs) with morphogenetic potential. SCs may be isolated from epidermal and mesenchymal compartments of HF. Additionally neural crest-derived cells are found in HF, at least in the facial skin [9, 10]. Matrix cells had been thought to be stem cells for a long time as they proliferate very intensively at the beginning of the growth phase. However in experiments with murine HFs, Cotsarelis and co-authors discovered special population of cells at the bottom of a permanent portion of the HF known as the bulge [11]. These cells retained thymidine DNA label after 4 weeks of chase period unlike matrix cells which lost the label as early as 1 week after cessation of labeling. From these pioneering experiments, the bulge has been proved in many studies to be the main reservoir of SCs in HF. It contains morphologically undifferentiated and slow-cycling under the normal conditions of cells. The bulge is a swelling and contiguous part of outer root sheath. As many HFs lack anatomically well-defined bulge region, the term 'bulge' is often referred loosely to the permanent region of the follicle below the sebaceous gland [12, 13]. The bulge region is also the point of attachment of the arrector pilorum muscles [11]. SCs of melanocyte lineage are located in close proximity of the bulge epithelial SCs. Melanocyte proliferation and differentiation is strongly coordinated with the HF cycle. In fact, both types of SCs occupy the same niche or two partially overlapping niches [14, 15]. The arrector pilorum muscle is tightly connected with the bulge region. Epithelial SCs of the outer root sheath deposit nefronectin onto underlying basement membrane and regulate adhesion of mesenchymal cells expressing the receptor to nefronectin. Thus, bulge SC create the niche for smooth muscle cells and participate in regulation of the arrector pilorum muscle [16].

Epithelial and mesenchymal SCs of HF are not only a source of cell mass during HF regrowth phase, but they are also key regulators of hair cycle. Both pools of SCs produced multiple growth factors and cytokines regulating cellular proliferation, differentiation, and HF morphogenesis. Key regulators of hair cycle belong to Wnt, TGFbeta, FGF, and some other signaling pathway families [17, 18].

Bulge cells remain dormant during telogen. The DP plays a pivotal role in initiation of the next cycle of HF formation and hair growth [19–21]. This is associated with bulge cell migration and proliferation in the hair germ to generate the highly proliferative cells at the base of the follicle [7, 22]. Hair germ likely represents a special subpopulation of bulge descendants capable of quick recruitment into intensively proliferating state [7]. The authors suggest that the crosstalk between hair germ and DP via FGF7 signaling contributes significantly to the early steps of hair cycle activation.
