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Aging, Graying and Loss of Melanocyte Stem Cells


Hair graying is one of the prototypical signs of human aging. Maintenance of hair pigmentation is dependent on the presence and functionality of melanocytes, neural crest derived cells which synthesize pigment for growing hair. The melanocytes, themselves, are maintained by a small number of stem cells which reside in the bulge region of the hair follicle. The recent characterization of the melanocyte lineage during aging has significantly accelerated our understanding of how age-related changes in the melanocyte stem cell compartment contribute to hair graying. This review will discuss our current understanding of hair graying, drawing on evidence from human and mouse studies, and consider the contribution of melanocyte stem cells to this process. Furthermore, using the melanocyte lineage as an example, it will discuss common theories of tissue and stem cell aging.

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  1. 1.

    Allsopp, R. C., Morin, G. B., DePinho, R., Harley, C. B., & Weissman, I. L. (2003). Telomerase is required to slow telomere shortening and extend replicative lifespan of HSCs during serial transplantation. Blood, 102, 517–520.

    PubMed  Article  CAS  Google Scholar 

  2. 2.

    Arck, P. C., Overall, R., Spatz, K., Liezman, C., Handjiski, B., Klapp, B. F., et al. (2006). Towards a “free radical theory of graying”: Melanocyte apoptosis in the aging human hair follicle is an indicator of oxidative stress induced tissue damage. FASEB Journal, 20, 1567–1569.

    PubMed  Article  CAS  Google Scholar 

  3. 3.

    Bandyopadhyay, D., & Medrano, E. E. (2003). The emerging role of epigenetics in cellular and organismal aging. Experimental Gerontology, 38, 1299–1307.

    PubMed  Article  CAS  Google Scholar 

  4. 4.

    Barsh, G. S. (1996). The genetics of pigmentation: From fancy genes to complex traits. Trends in Genetics, 12, 299–305.

    PubMed  Article  CAS  Google Scholar 

  5. 5.

    Blackburn, E. H. (2001). Switching and signaling at the telomere. Cell, 106, 661–673.

    PubMed  Article  CAS  Google Scholar 

  6. 6.

    Blanpain, C., Horsley, V., & Fuchs, E. (2007). Epithelial stem cells: Turning over new leaves. Cell, 128, 445–458.

    PubMed  Article  CAS  Google Scholar 

  7. 7.

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

    PubMed  Article  CAS  Google Scholar 

  8. 8.

    Botchkareva, N. V., Khlgatian, M., Longley, B. J., Botchkarev, V. A., & Gilchrest, B. A. (2001). SCF/c-kit signaling is required for cyclic regeneration of the hair pigmentation unit. FASEB Journal, 15, 645–658.

    PubMed  Article  CAS  Google Scholar 

  9. 9.

    Cable, J., Jackson, I. J., & Steel, K. P. (1995). Mutations at the W locus affect survival of neural crest-derived melanocytes in the mouse. Mechanisms of Development, 50, 139–150.

    PubMed  Article  CAS  Google Scholar 

  10. 10.

    Chang, S., Multani, A. S., Cabrera, N. G., Naylor, M. L., Laud, P., Lombard, D., et al. (2004). Essential role of limiting telomeres in the pathogenesis of Werner syndrome. Nature Genetics, 36, 877–882.

    PubMed  Article  CAS  Google Scholar 

  11. 11.

    Chin, L., Artandi, S. E., Shen, Q., Tam, A., Lee, S. L., Gottlieb, G. J., et al. (1999). p53 Deficiency rescues the adverse effects of telomere loss and cooperates with telomere dysfunction to accelerate carcinogenesis. Cell, 97, 527–538.

    PubMed  Article  CAS  Google Scholar 

  12. 12.

    Commo, S., Gaillard, O., & Bernard, B. A. (2004). Human hair greying is linked to a specific depletion of hair follicle melanocytes affecting both the bulb and the outer root sheath. British Journal of Dermatology, 150, 435–443.

    PubMed  Article  CAS  Google Scholar 

  13. 13.

    Conboy, I. M., Conboy, M. J., Wagers, A. J., Girma, E. R., Weissman, I. L., & Rando, T. A. (2005). Rejuvenation of aged progenitor cells by exposure to a young systemic environment. Nature, 433, 760–764.

    PubMed  Article  CAS  Google Scholar 

  14. 14.

    Conboy, I. M., & Rando, T. A. (2005). Aging, stem cells and tissue regeneration: Lessons from muscle. Cell Cycle, 4, 407–410.

    PubMed  CAS  Google Scholar 

  15. 15.

    d’Adda di Fagagna, F., Reaper, P. M., Clay-Farrace, L., Fiegler, H., Carr, P., Von Zglinicki, T., et al. (2003). A DNA damage checkpoint response in telomere-initiated senescence. Nature, 426, 194–198.

    PubMed  Article  CAS  Google Scholar 

  16. 16.

    Globerson, A. (1999). Hematopoietic stem cells and aging. Experimental Gerontology, 34, 137–146.

    PubMed  Article  CAS  Google Scholar 

  17. 17.

    Gosain, A., & DiPietro, L. A. (2004). Aging and wound healing. World Journal of Surgery, 28, 321–326.

    PubMed  Article  Google Scholar 

  18. 18.

    Hemesath, T. J., Steingrimsson, E., McGill, G., Hansen, M. J., Vaught, J., Hodgkinson, C. A., et al. (1994). Microphthalmia, a critical factor in melanocyte development, defines a discrete transcription factor family. Genes & Development, 8, 2770–2780.

    Article  CAS  Google Scholar 

  19. 19.

    Johnson, R., & Jackson, I. J. (1992). Light is a dominant mouse mutation resulting in premature cell death. Nature Genetics, 1, 226–229.

    PubMed  Article  CAS  Google Scholar 

  20. 20.

    Karlseder, J., Broccoli, D., Dai, Y., Hardy, S., & de Lange, T. (1999). p53-and ATM-dependent apoptosis induced by telomeres lacking TRF2. Science, 283, 1321–1325.

    PubMed  Article  CAS  Google Scholar 

  21. 21.

    Kiger, A. A., Jones, D. L., Schulz, C., Rogers, M. B., & Fuller, M. T. (2001). Stem cell self-renewal specified by JAK-STAT activation in response to a support cell cue. Science, 294, 2542–2545.

    PubMed  Article  CAS  Google Scholar 

  22. 22.

    Kunisada, T., Yoshida, H., Yamazaki, H., Miyamoto, A., Hemmi, H., Nishimura, E., et al. (1998). Transgene expression of steel factor in the basal layer of epidermis promotes survival, proliferation, differentiation and migration of melanocyte precursors. Development, 125, 2915–2923.

    PubMed  CAS  Google Scholar 

  23. 23.

    Kurita, K., Nishito, M., Shimogaki, H., Takada, K., Yamazaki, H., & Kunisada, T. (2005). Suppression of progressive loss of coat color in microphthalmia-vitiligo mutant mice. Journal of Investigative Dermatology, 125, 538–544.

    PubMed  Article  CAS  Google Scholar 

  24. 24.

    Lamoreux, M. L., Boissy, R. E., Womack, J. E., & Nordlund, J. J. (1992). The Vit gene maps to the Mi (Microphthalmia) locus of the laboratory mouse. Journal of Heredity, 83, 435–439.

    PubMed  CAS  Google Scholar 

  25. 25.

    Lee, H. W., Blasco, M. A., Gottlieb, G. J., Horner, J. W., Greider, C. W., & DePinho, R. A. (1998). Essential role of mouse telomerase in highly proliferative organs. Nature, 392, 569–574.

    PubMed  Article  CAS  Google Scholar 

  26. 26.

    Lerner, A. B., Shiohara, T., Boissy, R. E., Jacobson, K. A., Lamoreux, M. L., & Moellmann, G. E. (1986). A mouse model for vitiligo. Journal of Investigative Dermatology, 87, 299–304.

    PubMed  Article  CAS  Google Scholar 

  27. 27.

    Mackenzie, M. A., Jordan, S. A., Budd, P. S., & Jackson, I. J. (1997). Activation of the receptor tyrosine kinase kit is required for the proliferation of melanoblasts in the mouse embryo. Developments in Biologicals, 192, 99–107.

    CAS  Google Scholar 

  28. 28.

    Mak, S. S., Moriyama, M., Nishioka, E., Osawa, M., & Nishikawa, S. (2006). Indispensable role of Bcl2 in the development of the melanocyte stem cell. Developments in Biologicals, 291, 144–153.

    CAS  Google Scholar 

  29. 29.

    McGill, G. G., Horstmann, M., Widlund, H. R., Du, J., Motyckova, G., Nishimura, E. K., et al. (2002). Bcl2 regulation by the melanocyte master regulator mitf modulates lineage survival and melanoma cell viability. Cell, 109, 707–718.

    PubMed  Article  CAS  Google Scholar 

  30. 30.

    Murphy, M., Reid, K., Williams, D. E., Lyman, S. D., & Bartlett, P. F. (1992). Steel factor is required for maintenance, but not differentiation, of melanocyte precursors in the neural crest. Developments in Biologicals, 153, 396–401.

    CAS  Article  Google Scholar 

  31. 31.

    Nishikawa, S., Kusakabe, M., Yoshinaga, K., Ogawa, M., Hayashi, S., Kunisada, T., et al. (1991). In utero manipulation of coat color formation by a monoclonal anti-c-kit antibody: Two distinct waves of c-kit-dependency during melanocyte development. EMBO Journal, 10, 2111–2118.

    PubMed  CAS  Google Scholar 

  32. 32.

    Nishimura, E. K., Granter, S. R., & Fisher, D. E. (2005). Mechanisms of hair graying: Incomplete melanocyte stem cell maintenance in the niche. Science, 307, 720–724.

    PubMed  Article  CAS  Google Scholar 

  33. 33.

    Nishimura, E. K., Jordan, S. A., Oshima, H., Yoshida, H., Osawa, M., Moriyama, M., et al. (2002). Dominant role of the niche in melanocyte stem-cell fate determination. Nature, 416, 854–860.

    PubMed  Article  CAS  Google Scholar 

  34. 34.

    Osawa, M., Egawa, G., Mak, S. S., Moriyama, M., Freter, R., Yonetani, S., et al. (2005). Molecular characterization of melanocyte stem cells in their niche. Development, 132, 5589–5599.

    PubMed  Article  CAS  Google Scholar 

  35. 35.

    Quevedo, W. C., Szabo, G., & Virks, J. (1969). Influence of age and UV on the populations of dopa-positive melanocytes in human skin. Journal of Investigative Dermatology, 52, 287–290.

    PubMed  CAS  Google Scholar 

  36. 36.

    Rando, T. A. (2006). Stem cells, ageing and the quest for immortality. Nature, 441, 1080–1086.

    PubMed  Article  CAS  Google Scholar 

  37. 37.

    Rossi, D. J., Bryder, D., & Weissman, I. L. (2007). Hematopoietic stem cell aging: Mechanism and consequence. Experimental Gerontology, 42, 385–390.

    PubMed  Article  CAS  Google Scholar 

  38. 38.

    Rudolph, K. L., Chang, S., Lee, H. W., Blasco, M., Gottlieb, G. J., Greider, C., et al. (1999). Longevity, stress response, and cancer in aging telomerase-deficient mice. Cell, 96, 701–712.

    PubMed  Article  CAS  Google Scholar 

  39. 39.

    Sharpless, N. E., & DePinho, R. A. (2004). Telomeres, stem cells, senescence, and cancer. Journal of Clinical Investigation, 113, 160–168.

    PubMed  Article  CAS  Google Scholar 

  40. 40.

    Slominski, A., & Paus, R. (1993). Melanogenesis is coupled to murine anagen: Toward new concepts for the role of melanocytes and the regulation of melanogenesis in hair growth. Journal of Investigative Dermatology, 101, 90S–97S.

    PubMed  Article  CAS  Google Scholar 

  41. 41.

    Spradling, A., Drummond-Barbosa, D., & Kai, T. (2001). Stem cells find their niche. Nature, 414, 98–104.

    PubMed  Article  CAS  Google Scholar 

  42. 42.

    Steingrimsson, E., Copeland, N. G., & Jenkins, N. A. (2005). Melanocyte stem cell maintenance and hair graying. Cell, 121, 9–12.

    PubMed  Article  CAS  Google Scholar 

  43. 43.

    Takai, H., Smogorzewska, A., & de Lange, T. (2003). DNA damage foci at dysfunctional telomeres. Current Biology, 13, 1549–1556.

    PubMed  Article  CAS  Google Scholar 

  44. 44.

    Tobin, D. J., & Bystryn, J. C. (1996). Different populations of melanocytes are present in hair follicles and epidermis. Pigment Cell Research, 9, 304–310.

    PubMed  Article  CAS  Google Scholar 

  45. 45.

    Tobin, D. J., & Paus, R. (2001). Graying: Gerontobiology of the hair follicle pigmentary unit. Experimental Gerontology, 36, 29–54.

    PubMed  Article  CAS  Google Scholar 

  46. 46.

    Tumbar, T., Guasch, G., Greco, V., Blanpain, C., Lowry, W. E., Rendl, M., et al. (2004). Defining the epithelial stem cell niche in skin. Science, 303, 359–363.

    PubMed  Article  CAS  Google Scholar 

  47. 47.

    Van Zant, G., & Liang, Y. (2003). The role of stem cells in aging. Experimental Hematology, 31, 659–672.

    PubMed  Article  CAS  Google Scholar 

  48. 48.

    Veis, D. J., Sorenson, C. M., Shutter, J. R., & Korsmeyer, S. J. (1993). Bcl-2-deficient mice demonstrate fulminant lymphoid apoptosis, polycystic kidneys, and hypopigmented hair. Cell, 75, 229–240.

    PubMed  Article  CAS  Google Scholar 

  49. 49.

    Wehrle-Haller, B., & Weston, J. A. (1995). Soluble and cell-bound forms of steel factor activity play distinct roles in melanocyte precursor dispersal and survival on the lateral neural crest migration pathway. Development, 121, 731–742.

    PubMed  CAS  Google Scholar 

  50. 50.

    Yoshida, H., Kunisada, T., Grimm, T., Nishimura, E. K., Nishioka, E., & Nishikawa, S. I. (2001). Review: Melanocyte migration and survival controlled by SCF/c-kit expression. Journal of Investigative Dermatology Symposium Proceedings, 6, 1–5.

    Article  CAS  Google Scholar 

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Correspondence to Steven E. Artandi.

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Sarin, K.Y., Artandi, S.E. Aging, Graying and Loss of Melanocyte Stem Cells. Stem Cell Rev 3, 212–217 (2007).

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  • Stem cells
  • Aging
  • Pigmentation
  • Graying
  • Melanocytes
  • Telomeres
  • Bcl2
  • Vitiligo
  • Light mutation