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.
Subscribe to Journal
Get full journal access for 1 year
only $18.75 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
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).
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).
Mackenzie, I.C. Retroviral transduction of murine epidermal stem cells demonstrates clonal units of epidermal structure. J. Invest. Dermatol. 109, 377–383 (1997).
Potten, C.S. The epidermal proliferative unit: the possible role of the central basal cell. Cell Tissue Kinet. 7, 77–88 (1974).
Fuchs, E., Tumbar, T. & Guasch, G. Socializing with the neighbors: stem cells and their niche. Cell 116, 769–778 (2004).
Lavker, R.M. & Sun, T.T. Epidermal stem cells: properties, markers, and location. Proc. Natl. Acad. Sci. USA 97, 13473–13475 (2000).
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).
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).
Morris, R.J. et al. Capturing and profiling adult hair follicle stem cells. Nat. Biotechnol. 22, 411–417 (2004).
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).
Tumbar, T. et al. Defining the epithelial stem cell niche in skin. Science 303, 359–363 (2004).
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).
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).
Argyris, T. Kinetics of epidermal production during epidermal regeneration following abrasion in mice. Am. J. Pathol. 83, 329–340 (1976).
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).
Morasso, M.I. & Tomic-Canic, M. Epidermal stem cells: the cradle of epidermal determination, differentiation and wound healing. Biol. Cell. 97, 173–183 (2005).
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).
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).
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).
Watt, F.M. & Hogan, B.L. Out of Eden: stem cells and their niches. Science 287, 1427–1430 (2000).
Fraidenraich, D. et al. Rescue of cardiac defects in id knockout embryos by injection of embryonic stem cells. Science 306, 247–252 (2004).
Mackenzie, I.C. Relationship between mitosis and the ordered structure of the stratum corneum in mouse epidermis. Nature 226, 653–655 (1970).
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).
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).
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).
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).
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).
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).
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.).
The authors declare no competing financial interests.
Incisional wounding results. (PDF 246 kb)
Tape stripping results. (PDF 361 kb)
Bulge-derived cells transiently repopulate reepithelialized epidermis. (PDF 541 kb)
Epidermal markers in bulge-derived cells. (PDF 79 kb)
Percentage of lacZ-positive cells remains constant over time. (PDF 15 kb)
About this article
Cite this article
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) doi:10.1038/nm1328
Proceedings of the National Academy of Sciences (2019)
Nature Reviews Drug Discovery (2019)
Induction of hair follicle neogenesis with cultured mouse dermal papilla cells in de novo regenerated skin tissues
Journal of Tissue Engineering and Regenerative Medicine (2019)
Expert Opinion on Biological Therapy (2019)
Physiological Reviews (2019)