Cyclic dermal BMP signaling regulates stem cell activation during hair regeneration

In the age of stem cell engineering, it is critical to understand how stem cell activity is regulated during regeneration. Hairs are mini-organs that undergo cyclic regeneration throughout adult life,1 and are an important model for organ regeneration. Hair stem cells located in the follicle bulge2 are regulated by the surrounding micro-environment, or niche3. The activation of such stem cells is cyclic, involving periodic β-catenin activity4–7. In adult mouse, regeneration occurs in waves in a follicle population, implying coordination among adjacent follicles and the extra-follicular environment. Here we show unexpected periodic expression of Bmp2/4 in the dermis regulates this process. This Bmp cycle is out-of-phase with the Wnt/β-catenin cycle, thus dividing the conventional telogen into new functional phases: one refractory and the other competent for hair regeneration; characterized by high and low Bmp signaling respectively. Over-expression of noggin, a Bmp antagonist, in mouse skin resulted in a dramatically shortened refractory phase and faster propagation of the regenerative wave. Transplantation of skin from this mutant onto a wild type host showed that follicles in donor and host can affect their cycling behaviors mutually, with the outcome depending on the equilibrium of Bmp activity in the dermis. Administration of BMP protein caused the competent region to become refractory. These results show that Bmps may be the long-sought “chalone” inhibitors of hair growth postulated by classical experiments. Taken together, results presented in this study provide an example of hierarchical regulation of local organ stem cell homeostasis by inter-organ macro-environment. The expression of Bmp2 in subcutaneous adipocytes suggests physiological integration between these two thermo-regulatory organs. Our findings have practical importance to those using mouse skin as a model for carcinogenesis, intra-cutaneous drug delivery and stem cell engineering studies, as they highlight the acute need to differentiate supportive versus inhibitory regions in the host skin.