Cyclic dermal BMP signalling regulates stem cell activation during hair regeneration

Article metrics


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.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1: Defining refractory and competent telogen.
Figure 2: Periodic BMP signalling in the dermis and subcutaneous adipose tissue.
Figure 3: Altered hair regenerative wave dynamics in Krt14–Nog mice, and non-autonomous interactions with normal cycling host skin after transplantation.
Figure 4: Functional phases of the hair cycle.


  1. 1

    Stenn, K. S. & Paus, R. Controls of hair follicle cycling. Physiol. Rev. 81, 449–494 (2001)

  2. 2

    Morris, R. J. et al. Capturing and profiling adult hair follicle stem cells. Nature Biotechnol. 22, 411–417 (2004)

  3. 3

    Fuchs, E., Tumbar, T. & Guasch, G. Socializing with the neighbors: stem cells and their niche. Cell 116, 769–778 (2004)

  4. 4

    Huelsken, J., Vogel, R., Erdmann, B., Cotsarelis, G. & Birchmeier, W. β-Catenin controls hair follicle morphogenesis and stem cell differentiation in the skin. Cell 105, 533–545 (2001)

  5. 5

    Reddy, S. et al. Characterization of Wnt gene expression in developing and postnatal hair follicles and identification of Wnt5a as a target of Sonic hedgehog in hair follicle morphogenesis. Mech. Dev. 107, 69–82 (2001)

  6. 6

    Lo Celso, C., Prowse, D. M. & Watt, F. M. Transient activation of β-catenin signalling in adult mouse epidermis is sufficient to induce new hair follicles but continuous activation is required to maintain hair follicle tumours. Development 131, 1787–1799 (2004)

  7. 7

    Lowry, W. E. et al. Defining the impact of β-catenin/Tcf transactivation on epithelial stem cells. Genes Dev. 19, 1596–1611 (2005)

  8. 8

    Moore, K. A. & Lemischka, I. R. Stem cells and their niches. Science 311, 1880–1885 (2006)

  9. 9

    Ma, L. et al. ‘Cyclic alopecia’ in Msx2 mutants: defects in hair cycling and hair shaft differentiation. Development 130, 379–389 (2003)

  10. 10

    Militzer, K. Hair growth pattern in nude mice. Cell. Tiss. Org. 168, 285–294 (2001)

  11. 11

    Suzuki, N., Hirata, M. & Kondo, S. Traveling stripes on the skin of a mutant mouse. Proc. Natl Acad. Sci. USA 100, 9680–9685 (2003)

  12. 12

    Durward, A. & Rudall, K. M. Studies on hair growth in the rat. J. Anat. 83, 325–335 (1949)

  13. 13

    Plikus, M. V. & Chuong, C. M. Complex hair cycle domain patterns and regenerative hair waves in living rodents. J. Invest. Dermatol. (in the press). (2007)

  14. 14

    Ebling, F. J. & Johnson, E. Systemic influence on activity of hair follicles in skin homografts. J. Embryol. Exp. Morphol. 9, 285–293 (1961)

  15. 15

    Chase, H. Growth of the hair. Physiol. Rev. 34, 113–126 (1954)

  16. 16

    Paus, R., Stenn, K. S. & Link, R. E. Telogen skin contains an inhibitor of hair growth. Br. J. Dermatol. 122, 777–784 (1990)

  17. 17

    Botchkarev, V. A. et al. Noggin is required for induction of the hair follicle growth phase in postnatal skin. FASEB J. 15, 2205–2214 (2001)

  18. 18

    Maurer, M., Handjiski, B. & Paus, R. Hair growth modulation by topical immunophilin ligands: induction of anagen, inhibition of massive catagen development, and relative protection from chemotherapy-induced alopecia. Am. J. Pathol. 150, 1433–1441 (1997)

  19. 19

    Johnson, E. Quantitative studies of hair growth in the albino rat. II. The effect of sex hormones. J. Endocrinol. 16, 351–359 (1958)

  20. 20

    Botchkarev, V. A. et al. Noggin is a mesenchymally derived stimulator of hair-follicle induction. Nature Cell Biol. 1, 158–164 (1999)

  21. 21

    Kobielak, K., Stokes, N., de la Cruz, J., Polak, L. & Fuchs, E. Loss of a quiescent niche but not follicle stem cells in the absence of bone morphogenetic protein signaling. Proc. Natl Acad. Sci. USA 104, 10063–10068 (2007)

  22. 22

    Blanpain, C., Lowry, W. E., Geoghegan, A., Polak, L. & Fuchs, E. Self-renewal, multipotency, and the existence of two cell populations within an epithelial stem cell niche. Cell 118, 635–648 (2004)

  23. 23

    Plikus, M. et al. Morpho-regulation of ectodermal organs: integument pathology and phenotypic variations in K14-Noggin engineered mice through modulation of bone morphogenic protein pathway. Am. J. Pathol. 164, 1099–1114 (2004)

  24. 24

    Zhang, J. et al. Bone morphogenetic protein signaling inhibits hair follicle anagen induction by restricting epithelial stem/progenitor cell activation and expansion. Stem Cells 24, 2826–2839 (2006)

  25. 25

    Oro, A. E. & Higgins, K. Hair cycle regulation of Hedgehog signal reception. Dev. Biol. 255, 238–248 (2003)

  26. 26

    He, X. C. et al. BMP signaling inhibits intestinal stem cell self-renewal through suppression of Wnt–β-catenin signaling. Nature Genet. 36, 1117–1121 (2004)

  27. 27

    Iguchi, M., Aiba, S., Yoshino, Y. & Tagami, H. Human follicular papilla cells carry out nonadipose tissue production of leptin. J. Invest. Dermatol. 117, 1349–1356 (2001)

  28. 28

    Wu, P. et al. Evo-Devo of amniote integuments and appendages. Int. J. Dev. Biol. 48, 249–270 (2004)

  29. 29

    Sausville, E. A. & Burger, A. M. Contributions of human tumor xenografts to anticancer drug development. Cancer Res. 66, 3351–3354 (2006)

  30. 30

    Zheng, Y. et al. Organogenesis from dissociated cells: generation of mature cycling hair follicles from skin-derived cells. J. Invest. Dermatol. 124, 867–876 (2005)

Download references


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.

Author information

Correspondence to Cheng-Ming Chuong.

Supplementary information

Supplementary Figures

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)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

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

Download citation

Further reading


By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.