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 life1, and are an important model for organ regeneration. Hair stem cells located in the follicle bulge2 are regulated by the surrounding microenvironment, or niche3. The activation of such stem cells is cyclic, involving periodic β-catenin activity4,5,6,7. In the adult mouse, regeneration occurs in waves in a follicle population, implying coordination among adjacent follicles and the extrafollicular environment. Here we show that unexpected periodic expression of bone morphogenetic protein 2 (Bmp2) and Bmp4 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 signalling, respectively. Overexpression of noggin, a BMP antagonist, in mouse skin resulted in a markedly 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 behaviours mutually, with the outcome depending on the equilibrium of BMP activity in the dermis. Administration of BMP4 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 the inter-organ macroenvironment. The expression of Bmp2 in subcutaneous adipocytes indicates physiological integration between these two thermo-regulatory organs. Our findings have practical importance for studies using mouse skin as a model for carcinogenesis, intra-cutaneous drug delivery and stem cell engineering studies, because they highlight the acute need to differentiate supportive versus inhibitory regions in the host skin.
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We thank V. Botchkarev, G. Cotsarelis, B. Morgan, R. Paus, J. Sundberg and R. Widelitz for discussions. We are grateful to B. Hogan, R. Harland and S. Bellusci for providing transgenic mice. This work is supported by Grants from NIAMS and NIA from the NIH, USA, to C.-M.C. M.V.P. is a postdoctoral scholar of the California Institute of Regenerative Medicine. R.E.B. is supported by a Research Councils UK Fellowship and a Microsoft European Postdoctoral Research Fellowship.
Author Contributions M.V.P. and C.-M.C. designed the experiment and analysed results together. M.V.P. did major bench work and observations. J.A.M. and D.d.l.C. helped with some bench work. R.E.B. and P.K.M. helped to develop the model. R.M. helped by providing mice and discussing the results.
This file includes Supplementary Figures 1-10 with Legends. Supplementary Figure 1 contains model illustrating functional phases of the hair cycle. Supplementary Figures 2-11 illustrate various aspects of the results, including expression data, transplantation experiments, and other functional experiments. (PDF 4123 kb)
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Plikus, M., Mayer, J., de la Cruz, D. et al. Cyclic dermal BMP signalling regulates stem cell activation during hair regeneration. Nature 451, 340–344 (2008) doi:10.1038/nature06457
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