Cells within the bulge region of mouse hair follicle transiently proliferate during early anagen: heterogeneity and functional differences of various hair cycles

Based on cell kinetic, morphological and several biological considerations, we have recently proposed that hair follicle stem cells reside in the bulge area of the upper follicle. We predicted that during early anagen the normally slow-cycling bulge stem cells may be activated by the abutting dermal papilla cells to undergo transient proliferation giving rise to keratinocytes of the lower follicle. In the present work, we performed tritiated thymidine-labeling of DNA-synthesizing cells and colcemid-arrest of mitotic figures on the skins of 20-23 and 75-80 day old SENCAR mice, when the follicles entered the anagen phase of the 2nd and 3rd hair cycles. The results clearly indicate that the normally slow-cycling bulge cells indeed undergo transient proliferation during early anagen. Similar results were obtained when the telogen follicles are experimentally induced to enter the 3rd hair cycle by plucking and by topical applications of phorbol ester or tretinoin. These results support the notion that bulge cells are follicular stem cells, and that transient proliferation of these cells is a critical feature of early anagen. However, the long duration of the 2nd telogen (> 30 days in mouse) suggests that a new anagen phase does not automatically result from the physical proximity of dermal papilla to the bulge cells, and that another 'factor' is required for the initiation of the 3rd anagen. The tremendous difference in the durations of the first and second telogen (lasting for 2-3 days and > 50 days, respectively) suggests that follicles can exist in a non-cycling state that may be conceptually equivalent to the G0 state of the cell cycle. Our results also underscore the fact that the first hair cycle is distinct from all the subsequent hair cycles in their cellular origin and morphological sequence, and thus should be regarded as a neogenic event.