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Stem cells in the hair follicle bulge contribute to wound repair but not to homeostasis of the epidermis

Nature Medicine volume 11, pages 1351–1354 (2005)Cite this article

Abstract

The discovery of long-lived epithelial stem cells in the bulge region of the hair follicle led to the hypothesis that epidermal renewal and epidermal repair after wounding both depend on these cells1. To determine whether bulge cells are necessary for epidermal renewal, here we have ablated these cells by targeting them with a suicide gene encoding herpes simplex virus thymidine kinase (HSV-TK) using a Keratin 1–15 (Krt1-15) promoter2. We show that ablation leads to complete loss of hair follicles but survival of the epidermis. Through fate-mapping experiments, we find that stem cells in the hair follicle bulge do not normally contribute cells to the epidermis which is organized into epidermal proliferative units, as previously predicted3,4. After epidermal injury, however, cells from the bulge are recruited into the epidermis and migrate in a linear manner toward the center of the wound, ultimately forming a marked radial pattern. Notably, although the bulge-derived cells acquire an epidermal phenotype, most are eliminated from the epidermis over several weeks, indicating that bulge stem cells respond rapidly to epidermal wounding by generating short-lived 'transient amplifying' cells responsible for acute wound repair. Our findings have implications for both gene therapy and developing treatments for wounds because it will be necessary to consider epidermal and hair follicle stem cells as distinct populations.

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Figure 1: Administration of ganciclovir to Krt1-15–HSV-TK mice injures hair follicle bulge cells.
Figure 2: Hair follicles in grafted Krt1-15–HSV-TK ROSA26 skin are destroyed, but epidermis survives, after administration of ganciclovir.
Figure 3: Bulge cells do not contribute to epidermal renewal under normal conditions.
Figure 4: Lineage analysis of bulge cells after wounding.

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References

  1. 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  Google Scholar 

  2. 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  Google Scholar 

  3. Mackenzie, I.C. Retroviral transduction of murine epidermal stem cells demonstrates clonal units of epidermal structure. J. Invest. Dermatol. 109, 377–383 (1997).

    Article  CAS  Google Scholar 

  4. Potten, C.S. The epidermal proliferative unit: the possible role of the central basal cell. Cell Tissue Kinet. 7, 77–88 (1974).

    CAS  PubMed  Google Scholar 

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

    Article  CAS  Google Scholar 

  6. Lavker, R.M. & Sun, T.T. Epidermal stem cells: properties, markers, and location. Proc. Natl. Acad. Sci. USA 97, 13473–13475 (2000).

    Article  CAS  Google Scholar 

  7. Lyle, S. et al. The C8/144B monoclonal antibody recognizes cytokeratin 15 and defines the location of human hair follicle stem cells. J. Cell Sci. 111, 3179–3188 (1998).

    CAS  PubMed  Google Scholar 

  8. Morris, R.J. & Potten, C.S. Highly persistent label-retaining cells in the hair follicles of mice and their fate following induction of anagen. J. Invest. Dermatol. 112, 470–475 (1999).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  10. 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  Google Scholar 

  11. Tumbar, T. et al. Defining the epithelial stem cell niche in skin. Science 303, 359–363 (2004).

    Article  CAS  Google Scholar 

  12. Oshima, H., Rochat, A., Kedzia, C., Kobayashi, K. & Barrandon, Y. Morphogenesis and renewal of hair follicles from adult multipotent stem cells. Cell 104, 233–245 (2001).

    Article  CAS  Google Scholar 

  13. Ghazizadeh, S. & Taichman, L.B. Multiple classes of stem cells in cutaneous epithelium: a lineage analysis of adult mouse skin. EMBO J. 20, 1215–1222 (2001).

    Article  CAS  Google Scholar 

  14. Argyris, T. Kinetics of epidermal production during epidermal regeneration following abrasion in mice. Am. J. Pathol. 83, 329–340 (1976).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Miller, S.J., Burke, E.M., Rader, M.D., Coulombe, P.A. & Lavker, R.M. Re-epithelialization of porcine skin by the sweat apparatus. J. Invest. Dermatol. 110, 13–19 (1998).

    Article  CAS  Google Scholar 

  16. Morasso, M.I. & Tomic-Canic, M. Epidermal stem cells: the cradle of epidermal determination, differentiation and wound healing. Biol. Cell. 97, 173–183 (2005).

    Article  CAS  Google Scholar 

  17. Borrelli, E., Heyman, R., Hsi, M. & Evans, R.M. Targeting of an inducible toxic phenotype in animal cells. Proc. Natl. Acad. Sci. USA 85, 7572–7576 (1988).

    Article  CAS  Google Scholar 

  18. 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).

    Article  CAS  Google Scholar 

  19. 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  Google Scholar 

  20. Watt, F.M. & Hogan, B.L. Out of Eden: stem cells and their niches. Science 287, 1427–1430 (2000).

    Article  CAS  Google Scholar 

  21. Fraidenraich, D. et al. Rescue of cardiac defects in id knockout embryos by injection of embryonic stem cells. Science 306, 247–252 (2004).

    Article  CAS  Google Scholar 

  22. Mackenzie, I.C. Relationship between mitosis and the ordered structure of the stratum corneum in mouse epidermis. Nature 226, 653–655 (1970).

    Article  CAS  Google Scholar 

  23. Ferraris, C., Chevalier, G., Favier, B., Jahoda, C.A. & Dhouailly, D. Adult corneal epithelium basal cells possess the capacity to activate epidermal, pilosebaceous and sweat gland genetic programs in response to embryonic dermal stimuli. Development 127, 5487–5495 (2000).

    CAS  PubMed  Google Scholar 

  24. Li, A., Pouliot, N., Redvers, R. & Kaur, P. Extensive tissue-regenerative capacity of neonatal human keratinocyte stem cells and their progeny. J. Clin. Invest. 113, 390–400 (2004).

    Article  CAS  Google Scholar 

  25. 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  Google Scholar 

  26. 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  Google Scholar 

  27. Domashenko, A., Gupta, S. & Cotsarelis, G. Efficient delivery of transgenes to human hair follicle progenitor cells using topical lipoplex. Nat. Biotechnol. 18, 420–423 (2000).

    Article  CAS  Google Scholar 

  28. Ito, M. & Kizawa, K. Expression of calcium-binding S100 proteins A4 and A6 in regions of the epithelial sac associated with the onset of hair follicle regeneration. J. Invest. Dermatol. 116, 956–963 (2001).

    Article  CAS  Google Scholar 

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Acknowledgements

We thank J. Richa for generating transgenic mice and L. Ash for preparation of histological sections. This work was supported by US National Institutes of Health grants AR46837 (to G.C.) and CA97957 (to R.J.M. and G.C.).

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Author notes

  1. Mayumi Ito and Yaping Liu: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Dermatology, Kligman Laboratories, University of Pennsylvania School of Medicine, M8 Stellar-Chance Building, 422 Curie Boulevard, Philadelphia, 19104, Pennsylvania, USA

    Mayumi Ito, Yaping Liu, Zaixin Yang, Jane Nguyen, Fan Liang & George Cotsarelis

  2. Departments of Dermatology and Pathology, Columbia University College of Physicians and Surgeons, 630 West 168th Street, New York, 10032, New York, USA

    Rebecca J Morris

Authors
  1. Mayumi Ito
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Correspondence to George Cotsarelis.

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Supplementary information

Supplementary Fig. 1

Incisional wounding results. (PDF 246 kb)

Supplementary Fig. 2

Tape stripping results. (PDF 361 kb)

Supplementary Fig. 3

Bulge-derived cells transiently repopulate reepithelialized epidermis. (PDF 541 kb)

Supplementary Fig. 4

Epidermal markers in bulge-derived cells. (PDF 79 kb)

Supplementary Table

Percentage of lacZ-positive cells remains constant over time. (PDF 15 kb)

Supplementary Note (PDF 42 kb)

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Ito, M., Liu, Y., Yang, Z. et al. Stem cells in the hair follicle bulge contribute to wound repair but not to homeostasis of the epidermis. Nat Med 11, 1351–1354 (2005). https://doi.org/10.1038/nm1328

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