Direct migration of follicular melanocyte stem cells to the epidermis after wounding or UVB irradiation is dependent on Mc1r signaling

Subjects

Abstract

During wound healing, stem cells provide functional mature cells to meet acute demands for tissue regeneration1. Simultaneously, the tissue must maintain a pool of stem cells to sustain its future regeneration capability. However, how these requirements are balanced in response to injury is unknown. Here we demonstrate that after wounding or ultraviolet type B irradiation, melanocyte stem cells (McSCs) in the hair follicle2 exit the stem cell niche before their initial cell division, potentially depleting the pool of these cells. We also found that McSCs migrate to the epidermis in a melanocortin 1 receptor (Mc1r)-dependent manner and differentiate into functional epidermal melanocytes, providing a pigmented protective barrier against ultraviolet irradiation over the damaged skin. These findings provide an example in which stem cell differentiation due to injury takes precedence over stem cell maintenance and show the potential for developing therapies for skin pigmentation disorders by manipulating McSCs.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1: McSCs migrate from the hair follicle niche to the epidermis in response to injury or UVB irradiation.
Figure 2: McSCs migrate directly from the hair follicle niche to the epidermis without proliferation.
Figure 3: McSCs in Mc1r mutant mice show defects in migration to the epidermis.
Figure 4: Epidermal melanocytes reconstitute McSCs in de novo hair follicles formed in the wound.

References

  1. 1

    Fuchs, E. Skin stem cells: rising to the surface. J. Cell Biol. 180, 273–284 (2008).

    CAS  Article  Google Scholar 

  2. 2

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

    CAS  Article  Google Scholar 

  3. 3

    Lin, J.Y. & Fisher, D.E. Melanocyte biology and skin pigmentation. Nature 445, 843–850 (2007).

    CAS  Article  Google Scholar 

  4. 4

    Hirobe, T. Histochemical survey of the distribution of the epidermal melanoblasts and melanocytes in the mouse during fetal and postnatal periods. Anat. Rec. 208, 589–594 (1984).

    CAS  Article  Google Scholar 

  5. 5

    Nishimura, E.K. Melanocyte stem cells: a melanocyte reservoir in hair follicles for hair and skin pigmentation. Pigment Cell Melanoma Res. 24, 401–410 (2011).

    CAS  Article  Google Scholar 

  6. 6

    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).

    CAS  Article  Google Scholar 

  7. 7

    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).

    CAS  Article  Google Scholar 

  8. 8

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

    CAS  Article  Google Scholar 

  9. 9

    Ito, M. 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).

    CAS  Article  Google Scholar 

  10. 10

    Ortonne, J.P., MacDonald, D.M., Micoud, A. & Thivolet, J. PUVA-induced repigmentation of vitiligo: a histochemical (split-DOPA) and ultrastructural study. Br. J. Dermatol. 101, 1–12 (1979).

    CAS  Article  Google Scholar 

  11. 11

    Cui, J., Shen, L.Y. & Wang, G.C. Role of hair follicles in the repigmentation of vitiligo. J. Invest. Dermatol. 97, 410–416 (1991).

    CAS  Article  Google Scholar 

  12. 12

    Zhao, S. & Overbeek, P.A. Tyrosinase-related protein 2 promoter targets transgene expression to ocular and neural crest-derived tissues. Dev. Biol. 216, 154–163 (1999).

    CAS  Article  Google Scholar 

  13. 13

    Tanimura, S. et al. Hair follicle stem cells provide a functional niche for melanocyte stem cells. Cell Stem Cell 8, 177–187 (2011).

    CAS  Article  Google Scholar 

  14. 14

    Rabanni, P. et al. Coordinated activation of Wnt in epithelial and melanocyte stem cells initiates pigmented hair regeneration. Cell 145, 941–955 (2011).

    Article  Google Scholar 

  15. 15

    Lang, D. et al. Pax3 functions at a nodal point in melanocyte stem cell differentiation. Nature 433, 884–887 (2005).

    CAS  Article  Google Scholar 

  16. 16

    Chin, L. et al. Essential role for oncogenic Ras in tumour maintenance. Nature 400, 468–472 (1999).

    CAS  Article  Google Scholar 

  17. 17

    Wilson, A. et al. Hematopoietic stem cells reversibly switch from dormancy to self-renewal during homeostasis and repair. Cell 135, 1118–1129 (2008).

    CAS  Article  Google Scholar 

  18. 18

    Blanpain, C. & Fuchs, E. Epidermal homeostasis: a balancing act of stem cells in the skin. Nat. Rev. Mol. Cell Biol. 10, 207–217 (2009).

    CAS  Article  Google Scholar 

  19. 19

    Robbins, L.S. et al. Pigmentation phenotypes of variant extension locus alleles result from point mutations that alter MSH receptor function. Cell 72, 827–834 (1993).

    CAS  Article  Google Scholar 

  20. 20

    Hunt, G., Kyne, S., Wakamatsu, K., Ito, S. & Thody, A.J. Nle4DPhe7 α-melanocyte–stimulating hormone increases the eumelanin:phaeomelanin ratio in cultured human melanocytes. J. Invest. Dermatol. 104, 83–85 (1995).

    CAS  Article  Google Scholar 

  21. 21

    Seong, I. et al. Sox10 controls migration of B16F10 melanoma cells through multiple regulatory target genes. PLoS ONE 7, e31477 (2012).

    CAS  Article  Google Scholar 

  22. 22

    Ito, N. et al. Human hair follicles display a functional equivalent of the hypothalamic-pituitary-adrenal axis and synthesize cortisol. FASEB J. 19, 1332–1334 (2005).

    CAS  Article  Google Scholar 

  23. 23

    Slominski, A., Wortsman, J., Luger, T., Paus, R. & Solomon, S. Corticotropin releasing hormone and proopiomelanocortin involvement in the cutaneous response to stress. Physiol. Rev. 80, 979–1020 (2000).

    CAS  Article  Google Scholar 

  24. 24

    Vukelic, S. et al. Cortisol synthesis in epidermis is induced by IL-1 and tissue injury. J. Biol. Chem. 286, 10265–10275 (2011).

    CAS  Article  Google Scholar 

  25. 25

    D'Orazio, J.A. et al. Topical drug rescue strategy and skin protection based on the role of Mc1r in UV-induced tanning. Nature 443, 340–344 (2006).

    CAS  Article  Google Scholar 

  26. 26

    Ito, M. et al. Wnt-dependent de novo hair follicle regeneration in adult mouse skin after wounding. Nature 447, 316–320 (2007).

    CAS  Article  Google Scholar 

  27. 27

    Lichti, U. et al. In vivo regulation of murine hair growth: insights from grafting defined cell populations onto nude mice. J. Invest. Dermatol. 101 (suppl.), 124S–129S (1993).

    CAS  Article  Google Scholar 

  28. 28

    Prouty, S.M., Lawrence, L. & Stenn, K.S. Fibroblast-dependent induction of a murine skin lesion with similarity to human common blue nevus. Am. J. Pathol. 148, 1871–1885 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. 29

    Pharoah, P.D. Shedding light on skin cancer. Nat. Genet. 40, 817–818 (2008).

    CAS  Article  Google Scholar 

  30. 30

    Gilchrest, B.A. Molecular aspects of tanning. J. Invest. Dermatol. 131, E14–E17 (2011).

    Article  Google Scholar 

  31. 31

    Inoue, K. et al. Stress augmented ultraviolet-irradiation–induced pigmentation. J. Invest. Dermatol. 121, 165–171 (2003).

    CAS  Article  Google Scholar 

  32. 32

    Bennett, D.C., Cooper, P.J. & Hart, I.R. A line of non-tumorigenic mouse melanocytes, syngeneic with the B16 melanoma and requiring a tumour promoter for growth. Int. J. Cancer 39, 414–418 (1987).

    CAS  Article  Google Scholar 

  33. 33

    Han, R., Baden, H.P., Brissette, J.L. & Weiner, L. Redefining the skin's pigmentary system with a novel tyrosinase assay. Pigment Cell Res. 15, 290–297 (2002).

    CAS  Article  Google Scholar 

Download references

Acknowledgements

Follicle-derived epidermal melanocytes were initially observed at G. Cotsarelis' laboratory at the University of Pennsylvania, and this work benefited greatly from the mentorship and generosity of G. Cotsarelis. We thank P. Manga at New York University (NYU) for valuable discussion and for providing melan-a cells and antibody to mouse tyrosinase. We thank E. Hernando's lab at NYU for the protocol of the melanocyte migration assay. We thank the Microscopy Core of NYU for use of confocal microscopes (NCRRS10 RR023704-01A1). M.T. is supported by the NYU Kimmel Stem Cell Center and NYSTEM training grant C026880. M.I. is supported by US National Institutes of Health National Institute of Arthritis and Musculoskeletal and Skin Diseases grant 1R01AR059768-01A1 and the Ellison Medical Foundation.

Author information

Affiliations

Authors

Contributions

W.C.C. performed experiments, interpreted data and wrote the manuscript. M.T., P.R., H.H., W.L. and Y.R.C. performed experiments and interpreted data. J.C. provided human skin and interpreted data. P.O. generated Trp2-lacZ mice and interpreted the data. M.I. performed experiments, interpreted data and wrote the manuscript.

Corresponding author

Correspondence to Mayumi Ito.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–8 (PDF 1059 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Chou, W., Takeo, M., Rabbani, P. et al. Direct migration of follicular melanocyte stem cells to the epidermis after wounding or UVB irradiation is dependent on Mc1r signaling. Nat Med 19, 924–929 (2013). https://doi.org/10.1038/nm.3194

Download citation

Further reading