Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

Wnt-dependent de novo hair follicle regeneration in adult mouse skin after wounding

Nature volume 447, pages 316–320 (2007)Cite this article

Abstract

The mammalian hair follicle is a complex ‘mini-organ’ thought to form only during development1; loss of an adult follicle is considered permanent. However, the possibility that hair follicles develop de novo following wounding was raised in studies on rabbits2,3, mice4 and even humans fifty years ago5. Subsequently, these observations were generally discounted because definitive evidence for follicular neogenesis was not presented6. Here we show that, after wounding, hair follicles form de novo in genetically normal adult mice. The regenerated hair follicles establish a stem cell population, express known molecular markers of follicle differentiation, produce a hair shaft and progress through all stages of the hair follicle cycle. Lineage analysis demonstrated that the nascent follicles arise from epithelial cells outside of the hair follicle stem cell niche, suggesting that epidermal cells in the wound assume a hair follicle stem cell phenotype. Inhibition of Wnt signalling after re-epithelialization completely abrogates this wounding-induced folliculogenesis, whereas overexpression of Wnt ligand in the epidermis increases the number of regenerated hair follicles. These remarkable regenerative capabilities of the adult support the notion that wounding induces an embryonic phenotype in skin, and that this provides a window for manipulation of hair follicle neogenesis by Wnt proteins. These findings suggest treatments for wounds, hair loss and other degenerative skin disorders.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Hair follicle regeneration recapitulates embryonic development.
Figure 2: Regenerated hair follicles originate from non-hair-follicle stem cells.
Figure 3: Functional hair follicle stem cells are re-established in regenerated hair follicles.
Figure 4: Hair follicle neogenesis requires Wnt signalling, and overexpression of Wnt potentiates de novo follicle formation.

Similar content being viewed by others

References

  1. Schmidt-Ullrich, R. & Paus, R. Molecular principles of hair follicle induction and morphogenesis. Bioessays 27, 247– 261 (2005)

    Article  CAS  PubMed  Google Scholar 

  2. Billingham, R. E. & Russell, P. S. Incomplete wound contracture and the phenomenon of hair neogenesis in rabbit's skin. Nature 177, 791– 792 (1956)

    Article  ADS  CAS  PubMed  Google Scholar 

  3. Breedis, C. Regeneration of hair follicles and sebaceous glands from epithelium of scars in the rabbit. Cancer Res. 14, 575– 579 (1954)

    CAS  PubMed  Google Scholar 

  4. Lacassagne, A. & Latarjet, R. Action of methylcholanthrene on certain scars of the skin in mice. Cancer Res. 6, 183– 188 (1946)

    CAS  PubMed  Google Scholar 

  5. Kligman, A. M. & Strauss, J. S. The formation of vellus hair follicles from human adult epidermis. J. Invest. Dermatol. 27, 19– 23 (1956)

    Article  CAS  PubMed  Google Scholar 

  6. Straile, W. E. in Advances in Biology of Skin Vol. 9 (eds Montagna, W. & Dobson, R.) 369– 391 (Pergamon Press, New York, 1967)

    Google Scholar 

  7. Cotsarelis, G. Epithelial stem cells: a folliculocentric view. J. Invest. Dermatol. 126, 1459– 1468 (2006)

    Article  CAS  PubMed  Google Scholar 

  8. McGowan, K. M. & Coulombe, P. A. Onset of keratin 17 expression coincides with the definition of major epithelial lineages during skin development. J. Cell Biol. 143, 469– 486 (1998)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Paus, R. et al. A comprehensive guide for the recognition and classification of distinct stages of hair follicle morphogenesis. J. Invest. Dermatol. 113, 523– 532 (1999)

    Article  CAS  PubMed  Google Scholar 

  10. Millar, S. E. An ideal society? Neighbors of diverse origins interact to create and maintain complex mini-organs in the skin. PLoS Biol. 3, e372 (2005)

    Article  PubMed  PubMed Central  Google Scholar 

  11. 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)

    Article  CAS  PubMed  Google Scholar 

  12. Cotsarelis, G., Sun, T. T. & Lavker, R. M. Label-retaining cells reside in the bulge area of pilosebaceous unit: implications for follicular stem cells, hair cycle, and skin carcinogenesis. Cell 61, 1329– 1337 (1990)

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  Google Scholar 

  14. Ito, M. et al. Stem cells in the hair follicle bulge contribute to wound repair but not to homeostasis of the epidermis. Nature Med. 11, 1351– 1354 (2005)

    Article  CAS  PubMed  Google Scholar 

  15. Levy, V., Lindon, C., Harfe, B. D. & Morgan, B. A. Distinct stem cell populations regenerate the follicle and interfollicular epidermis. Dev. Cell 9, 855– 861 (2005)

    Article  CAS  PubMed  Google Scholar 

  16. Liu, Y., Lyle, S., Yang, Z. & Cotsarelis, G. Keratin 15 promoter targets putative epithelial stem cells in the hair follicle bulge. J. Invest. Dermatol. 121, 963– 968 (2003)

    Article  CAS  PubMed  Google Scholar 

  17. Wunderlich, F. T., Wildner, H., Rajewsky, K. & Edenhofer, F. New variants of inducible Cre recombinase: a novel mutant of Cre–PR fusion protein exhibits enhanced sensitivity and an expanded range of inducibility. Nucleic Acids Res. 29, E47 (2001)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Claudinot, S., Nicolas, M., Oshima, H., Rochat, A. & Barrandon, Y. Long-term renewal of hair follicles from clonogenic multipotent stem cells. Proc. Natl Acad. Sci. USA 102, 14677– 14682 (2005)

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  19. Levy, V., Lindon, C., Zheng, Y., Harfe, B. D. & Morgan, B. A. Epidermal stem cells arise from the hair follicle after wounding. FASEB J. advance online publication, doi:10.1096/fj.06–6926com (25 January 2007)

  20. Taylor, G., Lehrer, M. S., Jensen, P. J., Sun, T. T. & Lavker, R. M. Involvement of follicular stem cells in forming not only the follicle but also the epidermis. Cell 102, 451– 461 (2000)

    Article  CAS  PubMed  Google Scholar 

  21. Fernandes, K. J. et al. A dermal niche for multipotent adult skin-derived precursor cells. Nature Cell Biol. 6, 1082– 1093 (2004)

    Article  CAS  PubMed  Google Scholar 

  22. Nishimura, E. K. et al. Dominant role of the niche in melanocyte stem-cell fate determination. Nature 416, 854– 860 (2002)

    Article  ADS  CAS  PubMed  Google Scholar 

  23. Andl, T., Reddy, S. T., Gaddapara, T. & Millar, S. E. WNT signals are required for the initiation of hair follicle development. Dev. Cell 2, 643– 653 (2002)

    Article  CAS  PubMed  Google Scholar 

  24. Van Mater, D., Kolligs, F. T., Dlugosz, A. A. & Fearon, E. R. Transient activation of β-catenin signaling in cutaneous keratinocytes is sufficient to trigger the active growth phase of the hair cycle in mice. Genes Dev. 17, 1219– 1224 (2003)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Kishimoto, J., Burgeson, R. E. & Morgan, B. A. Wnt signaling maintains the hair-inducing activity of the dermal papilla. Genes Dev. 14, 1181– 1185 (2000)

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Gat, U., DasGupta, R., Degenstein, L. & Fuchs, E. De Novo hair follicle morphogenesis and hair tumors in mice expressing a truncated β-catenin in skin. Cell 95, 605– 614 (1998)

    Article  CAS  PubMed  Google Scholar 

  27. 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)

    Article  CAS  PubMed  Google Scholar 

  28. Fathke, C. et al. Wnt signaling induces epithelial differentiation during cutaneous wound healing. BMC Cell Biol. 7, 4 (2006)

    Article  PubMed  PubMed Central  Google Scholar 

  29. Atala, A. Tissue engineering, stem cells and cloning: current concepts and changing trends. Expert Opin. Biol. Ther. 5, 879– 892 (2005)

    Article  CAS  PubMed  Google Scholar 

  30. Liu, F. et al. Wnt–β-catenin signaling initiates taste papilla development. Nature Genet. 39, 106– 112 (2006)

    Article  PubMed  Google Scholar 

  31. Handjiski, B. K., Eichmuller, S., Hofmann, U., Czarnetzki, B. M. & Paus, R. Alkaline phosphatase activity and localization during the murine hair cycle. Br. J. Dermatol. 131, 303– 310 (1994)

    Article  CAS  PubMed  Google Scholar 

  32. Ito, M., Kizawa, K., Hamada, K. & Cotsarelis, G. Hair follicle stem cells in the lower bulge form the secondary germ, a biochemically distinct but functionally equivalent progenitor cell population, at the termination of catagen. Differentiation 72, 548– 557 (2004)

    Article  PubMed  Google Scholar 

  33. Chu, E. Y. et al. Canonical WNT signaling promotes mammary placode development and is essential for initiation of mammary gland morphogenesis. Development 131, 4819– 4829 (2004)

    Article  CAS  PubMed  Google Scholar 

  34. Millar, S. E. et al. WNT signaling in the control of hair growth and structure. Dev. Biol. 207, 133– 149 (1999)

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by US National Institutes of Health and, in part, by a grant from the Pennsylvania Department of Health to G.C. We thank P. Sterling for his comments on the manuscript and L. Ash for preparation of histological sections.

Author information

Authors and Affiliations

  1. Department of Dermatology, Kligman Laboratories, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA,

    Mayumi Ito, Zaixin Yang, Thomas Andl, Chunhua Cui, Noori Kim, Sarah E. Millar & George Cotsarelis

Authors
  1. Mayumi Ito
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Zaixin Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Thomas Andl
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Chunhua Cui
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Noori Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Sarah E. Millar
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. George Cotsarelis
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to George Cotsarelis.

Ethics declarations

Competing interests

M.I. and G.C. are listed as inventors on a patent application related to wounding-induced hair follicle neogenesis and owned by the University of Pennsylvania. G.C. serves on the scientific advisory board and has equity in Follica, a start up company that has licensed the patent from the University of Pennsylvania

Supplementary information

Supplementary Information

This file contains Supplementary Tables 1-3 and Supplementary Figures 1-8 with Legends. (PDF 6710 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ito, M., Yang, Z., Andl, T. et al. Wnt-dependent de novo hair follicle regeneration in adult mouse skin after wounding. Nature 447, 316–320 (2007). https://doi.org/10.1038/nature05766

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature05766

This article is cited by

Comments

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.

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing