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Emerging interactions between skin stem cells and their niches

Abstract

The skin protects mammals from insults, infection and dehydration and enables thermoregulation and sensory perception. Various skin-resident cells carry out these diverse functions. Constant turnover of cells and healing upon injury necessitate multiple reservoirs of stem cells. Thus, the skin provides a model for studying interactions between stem cells and their microenvironments, or niches. Advances in genetic and imaging tools have brought new findings about the lineage relationships between skin stem cells and their progeny and about the mutual influences between skin stem cells and their niches. Such knowledge may offer novel avenues for therapeutics and regenerative medicine.

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Figure 1: The skin: an organ with a diverse array of cell types.
Figure 2: Interfollicular epidermis: architecture, signaling and lineages.
Figure 3: Hierarchical versus stochastic models of epidermal differentiation.
Figure 4: Hair follicle lineage and niche signals regulate hair follicle stem cells.
Figure 5: Signaling pathways in skin cancers.

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References

  1. Xie, T. & Spradling, A.C. A niche maintaining germ line stem cells in the Drosophila ovary. Science 290, 328–330 (2000).

    Article  CAS  PubMed  Google Scholar 

  2. Hsu, Y.-C., Pasolli, H.A. & Fuchs, E. Dynamics between stem cells, niche, and progeny in the hair follicle. Cell 144, 92–105 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Sato, T. et al. Paneth cells constitute the niche for Lgr5 stem cells in intestinal crypts. Nature 469, 415–418 (2011).

    Article  CAS  PubMed  Google Scholar 

  4. Hsu, Y.-C. & Fuchs, E. A family business: stem cell progeny join the niche to regulate homeostasis. Nat. Rev. Mol. Cell Biol. 13, 103–114 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Hsu, Y.-C., Li, L. & Fuchs, E. Transit-amplifying cells orchestrate stem cell activity and tissue regeneration. Cell 157, 935–949 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Fujiwara, H. et al. The basement membrane of hair follicle stem cells is a muscle cell niche. Cell 144, 577–589 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Vasioukhin, V., Degenstein, L., Wise, B. & Fuchs, E. The magical touch: genome targeting in epidermal stem cells induced by tamoxifen application to mouse skin. Proc. Natl. Acad. Sci. USA 96, 8551–8556 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. 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  PubMed  Google Scholar 

  9. Kolodka, T.M., Garlick, J.A. & Taichman, L.B. Evidence for keratinocyte stem cells in vitro: long term engraftment and persistence of transgene expression from retrovirus-transduced keratinocytes. Proc. Natl. Acad. Sci. USA 95, 4356–4361 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. 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  PubMed  PubMed Central  Google Scholar 

  11. Ghazizadeh, S. & Taichman, L.B. Organization of stem cells and their progeny in human epidermis. J. Invest. Dermatol. 124, 367–372 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Ro, S. & Rannala, B. A stop-EGFP transgenic mouse to detect clonal cell lineages generated by mutation. EMBO Rep. 5, 914–920 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Clayton, E. et al. A single type of progenitor cell maintains normal epidermis. Nature 446, 185–189 (2007).

    Article  CAS  PubMed  Google Scholar 

  14. Doupé, D.P., Klein, A.M., Simons, B.D. & Jones, P.H. The ordered architecture of murine ear epidermis is maintained by progenitor cells with random fate. Dev. Cell 18, 317–323 (2010).

    Article  CAS  PubMed  Google Scholar 

  15. Lim, X. et al. Interfollicular epidermal stem cells self-renew via autocrine Wnt signaling. Science 342, 1226–1230 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Mascré, G. et al. Distinct contribution of stem and progenitor cells to epidermal maintenance. Nature 489, 257–262 (2012).

    Article  CAS  PubMed  Google Scholar 

  17. Rheinwald, J.G. & Green, H. Serial cultivation of strains of human epidermal keratinocytes: the formation of keratinizing colonies from single cells. Cell 6, 331–343 (1975).

    Article  CAS  PubMed  Google Scholar 

  18. Rendl, M., Lewis, L. & Fuchs, E. Molecular dissection of mesenchymal-epithelial interactions in the hair follicle. PLoS Biol. 3, e331 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Lewis, D.A., Travers, J.B., Somani, A.K. & Spandau, D.F. The IGF-1/IGF-1R signaling axis in the skin: a new role for the dermis in aging-associated skin cancer. Oncogene 29, 1475–1485 (2010).

    Article  CAS  PubMed  Google Scholar 

  20. Sadagurski, M. et al. Insulin-like growth factor 1 receptor signaling regulates skin development and inhibits skin keratinocyte differentiation. Mol. Cell. Biol. 26, 2675–2687 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Guo, L., Yu, Q.C. & Fuchs, E. Targeting expression of keratinocyte growth factor to keratinocytes elicits striking changes in epithelial differentiation in transgenic mice. EMBO J. 12, 973–986 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Rheinwald, J.G. & Green, H. Epidermal growth factor and the multiplication of cultured human epidermal keratinocytes. Nature 265, 421–424 (1977).

    Article  CAS  PubMed  Google Scholar 

  23. Vassar, R. & Fuchs, E. Transgenic mice provide new insights into the role of TGF-alpha during epidermal development and differentiation. Genes Dev. 5, 714–727 (1991).

    Article  CAS  PubMed  Google Scholar 

  24. Ferby, I. et al. Mig6 is a negative regulator of EGF receptor-mediated skin morphogenesis and tumor formation. Nat. Med. 12, 568–573 (2006).

    Article  CAS  PubMed  Google Scholar 

  25. Jensen, K.B. & Watt, F.M. Single-cell expression profiling of human epidermal stem and transit-amplifying cells: Lrig1 is a regulator of stem cell quiescence. Proc. Natl. Acad. Sci. USA 103, 11958–11963 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Jones, P.H., Harper, S. & Watt, F.M. Stem cell patterning and fate in human epidermis. Cell 80, 83–93 (1995).

    Article  CAS  PubMed  Google Scholar 

  27. Jones, P.H. & Watt, F.M. Separation of human epidermal stem cells from transit amplifying cells on the basis of differences in integrin function and expression. Cell 73, 713–724 (1993).

    Article  CAS  PubMed  Google Scholar 

  28. Jensen, U.B., Lowell, S. & Watt, F.M. The spatial relationship between stem cells and their progeny in the basal layer of human epidermis: a new view based on whole-mount labelling and lineage analysis. Development 126, 2409–2418 (1999).

    CAS  PubMed  Google Scholar 

  29. Raghavan, S., Bauer, C., Mundschau, G. & Li, Q. Conditional ablation of β1 integrin in skin severe defects in epidermal proliferation, basement membrane formation, and hair follicle invagination. J. Cell Biol. 150, 1149–1160 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Georges-Labouesse, E. et al. Absence of integrin alpha 6 leads to epidermolysis bullosa and neonatal death in mice. Nat. Genet. 13, 370–373 (1996).

    Article  CAS  PubMed  Google Scholar 

  31. Dowling, J., Yu, Q.C. & Fuchs, E. β4 integrin is required for hemidesmosome formation, cell adhesion and cell survival. J. Cell Biol. 134, 559–572 (1996).

    Article  CAS  PubMed  Google Scholar 

  32. van der Neut, R., Krimpenfort, P., Calafat, J., Niessen, C.M. & Sonnenberg, A. Epithelial detachment due to absence of hemidesmosomes in integrin β4 null mice. Nat. Genet. 13, 366–369 (1996).

    Article  CAS  PubMed  Google Scholar 

  33. McGrath, J.A. et al. Altered laminin 5 expression due to mutations in the gene encoding the beta 3 chain (LAMB3) in generalized atrophic benign epidermolysis bullosa. J. Invest. Dermatol. 104, 467–474 (1995).

    Article  CAS  PubMed  Google Scholar 

  34. Benitah, S.A., Frye, M., Glogauer, M. & Watt, F.M. Stem cell depletion through epidermal deletion of Rac1. Science 309, 933–935 (2005).

    Article  CAS  PubMed  Google Scholar 

  35. Sen, G.L., Reuter, J.A., Webster, D.E., Zhu, L. & Khavari, P.A. DNMT1 maintains progenitor function in self-renewing somatic tissue. Nature 463, 563–567 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Luis, N.M. et al. Regulation of human epidermal stem cell proliferation and senescence requires polycomb- dependent and -independent functions of Cbx4. Cell Stem Cell 9, 233–246 (2011).

    Article  CAS  PubMed  Google Scholar 

  37. Frye, M. & Benitah, S.A. Chromatin regulators in mammalian epidermis. Semin. Cell Dev. Biol. 23, 897–905 (2012).

    Article  CAS  PubMed  Google Scholar 

  38. Ezhkova, E. et al. Ezh2 orchestrates gene expression for the stepwise differentiation of tissue-specific stem cells. Cell 136, 1122–1135 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Ezhkova, E. et al. EZH1 and EZH2 cogovern histone H3K27 trimethylation and are essential for hair follicle homeostasis and wound repair. Genes Dev. 25, 485–498 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Mejetta, S. et al. Jarid2 regulates mouse epidermal stem cell activation and differentiation. EMBO J. 30, 3635–3646 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Sen, G.L., Webster, D.E., Barragan, D.I., Chang, H.Y. & Khavari, P.A. Control of differentiation in a self-renewing mammalian tissue by the histone demethylase JMJD3. Genes Dev. 22, 1865–1870 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Mulder, K.W. et al. Diverse epigenetic strategies interact to control epidermal differentiation. Nat. Cell Biol. 14, 753–763 (2012).

    Article  CAS  PubMed  Google Scholar 

  43. Geyfman, M. et al. Brain and muscle Arnt-like protein-1 (BMAL1) controls circadian cell proliferation and susceptibility to UVB-induced DNA damage in the epidermis. Proc. Natl. Acad. Sci. USA 109, 11758–11763 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  44. Janich, P. et al. Human epidermal stem cell function is regulated by circadian oscillations. Cell Stem Cell 13, 745–753 (2013).

    Article  CAS  PubMed  Google Scholar 

  45. Watt, F.M. & Green, H. Stratification and terminal differentiation of cultured epidermal cells. Nature 295, 434–436 (1982).

    Article  CAS  PubMed  Google Scholar 

  46. Lechler, T. & Fuchs, E. Asymmetric cell divisions promote stratification and differentiation of mammalian skin. Nature 437, 275–280 (2005).

    Article  PubMed  PubMed Central  Google Scholar 

  47. Powell, B.C., Passmore, E.A., Nesci, A. & Dunn, S.M. The Notch signalling pathway in hair growth. Mech. Dev. 78, 189–192 (1998).

    Article  CAS  PubMed  Google Scholar 

  48. Pan, Y. et al. γ-secretase functions through notch signaling to maintain skin appendages but is not required for their patterning or initial morphogenesis. Dev. Cell 7, 731–743 (2004).

    Article  CAS  PubMed  Google Scholar 

  49. Blanpain, C., Lowry, W.E., Pasolli, H.A. & Fuchs, E. Canonical notch signaling functions as a commitment switch in the epidermal lineage. Genes Dev. 20, 3022–3035 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Demehri, S., Turkoz, A. & Kopan, R. Epidermal Notch1 loss promotes skin tumorigenesis by impacting the stromal microenvironment. Cancer Cell 16, 55–66 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Williams, S.E., Beronja, S., Pasolli, H.A. & Fuchs, E. Asymmetric cell divisions promote Notch-dependent epidermal differentiation. Nature 470, 353–358 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Lowell, S., JONES, P., Le Roux, I., Dunne, J. & Watt, F.M. Stimulation of human epidermal differentiation by delta-notch signalling at the boundaries of stem-cell clusters. Curr. Biol. 10, 491–500 (2000).

    Article  CAS  PubMed  Google Scholar 

  53. Ezratty, E.J. et al. A role for the primary cilium in notch signaling and epidermal differentiation during skin development. Cell 145, 1129–1141 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Greco, V. et al. A two-step mechanism for stem cell activation during hair regeneration. Cell Stem Cell 4, 155–169 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  57. Rompolas, P., Mesa, K.R. & Greco, V. Spatial organization within a niche as a determinant of stem-cell fate. Nature 502, 513–518 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Lien, W.-H. et al. In vivo transcriptional governance of hair follicle stem cells by canonical Wnt regulators. Nat. Cell Biol. 16, 179–190 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Plikus, M.V. et al. Cyclic dermal BMP signalling regulates stem cell activation during hair regeneration. Nature 451, 340–344 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Chi, W., Wu, E. & Morgan, B.A. Dermal papilla cell number specifies hair size, shape and cycling and its reduction causes follicular decline. Development 140, 1676–1683 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Rompolas, P. et al. Live imaging of stem cell and progeny behaviour in physiological hair-follicle regeneration. Nature 487, 496–499 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Oshimori, N. & Fuchs, E. Paracrine TGF-β signaling counterbalances bmp-mediated repressionin hair follicle stem cell activation. Cell Stem Cell 10, 63–75 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Festa, E. et al. Adipocyte lineage cells contribute to the skin stem cell niche to drive hair cycling. Cell 146, 761–771 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Choi, Y.S. et al. Distinct functions for Wnt/β-catenin in hair follicle stem cell proliferation and survival and interfollicular epidermal homeostasis. Cell Stem Cell 13, 720–733 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Enshell-Seijffers, D., Lindon, C., Kashiwagi, M. & Morgan, B.A. β-catenin activity in the dermal papilla regulates morphogenesis and regeneration of hair. Dev. Cell 18, 633–642 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Plikus, M.V. et al. Self-organizing and stochastic behaviors during the regeneration of hair stem cells. Science 332, 586–589 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Janich, P. et al. The circadian molecular clock creates epidermal stem cell heterogeneity. Nature 480, 209–214 (2011).

    Article  CAS  PubMed  Google Scholar 

  68. Lin, K.K. et al. Circadian clock genes contribute to the regulation of hair follicle cycling. PLoS Genet. 5, e1000573 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Plikus, M.V. et al. Local circadian clock gates cell cycle progression of transient amplifying cells during regenerative hair cycling. Proc. Natl. Acad. Sci. USA 110, E2106–E2115 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  71. Nishimura, E.K. et al. Key roles for transforming growth factor β in melanocyte stem cell maintenance. Cell Stem Cell 6, 130–140 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  74. Chang, C.-Y. et al. NFIB is a governor of epithelial-melanocyte stem cell behaviour in a shared niche. Nature 495, 98–102 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Adur, J., Takizawa, S., Uchide, T., Casco, V. & Saida, K. High doses of ultraviolet-C irradiation increases vasoactive intestinal contractor/endothelin-2 expression in keratinocytes of the newborn mouse epidermis. Peptides 28, 1083–1094 (2007).

    Article  CAS  PubMed  Google Scholar 

  76. Paus, R., Hofmann, U. & Eichmüller, S. Distribution and changing density of γ-δ T cells in murine skin during the induced hair cycle. Br. J. Dermatol. 130, 281–289 (1994).

    Article  CAS  PubMed  Google Scholar 

  77. Paus, R. et al. Generation and cyclic remodeling of the hair follicle immune system in mice. J. Invest. Dermatol. 111, 7–18 (1998).

    Article  CAS  PubMed  Google Scholar 

  78. Jameson, J. et al. A role for skin γδ T cells in wound repair. Science 296, 747–749 (2002).

    Article  CAS  PubMed  Google Scholar 

  79. Sharp, L.L., Jameson, J.M., Cauvi, G. & Havran, W.L. Dendritic epidermal T cells regulate skin homeostasis through local production of insulin-like growth factor 1. Nat. Immunol. 6, 73–79 (2005).

    Article  CAS  PubMed  Google Scholar 

  80. Gay, D. et al. Fgf9 from dermal γδ T cells induces hair follicle neogenesis after wounding. Nat. Med. 19, 916–923 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Toulon, A. et al. A role for human skin-resident T cells in wound healing. J. Exp. Med. 206, 743–750 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Perez-Moreno, M. et al. p120-catenin mediates inflammatory responses in the skin. Cell 124, 631–644 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Nagao, K. et al. Stress-induced production of chemokines by hair follicles regulates the trafficking of dendritic cells in skin. Nat. Immunol. 13, 744–752 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Meyer, K.C. et al. Evidence that the bulge region is a site of relative immune privilege in human hair follicles. Br. J. Dermatol. 159, 1077–1085 (2008).

    CAS  PubMed  Google Scholar 

  85. Christoph, T. et al. The human hair follicle immune system: cellular composition and immune privilege. Br. J. Dermatol. 142, 862–873 (2000).

    Article  CAS  PubMed  Google Scholar 

  86. Kang, H. et al. Hair follicles from alopecia areata patients exhibit alterations in immune privilege-associated gene expression in advance of hair loss. J. Invest. Dermatol. 130, 2677–2680 (2010).

    Article  CAS  PubMed  Google Scholar 

  87. Al-Refu, K., Edward, S., Ingham, E. & Goodfield, M. Expression of hair follicle stem cells detected by cytokeratin 15 stain: implications for pathogenesis of the scarring process in cutaneous lupus erythematosus. Br. J. Dermatol. 160, 1188–1196 (2009).

    Article  CAS  PubMed  Google Scholar 

  88. Mobini, N., Tam, S. & Kamino, H. Possible role of the bulge region in the pathogenesis of inflammatory scarring alopecia: lichen planopilaris as the prototype. J. Cutan. Pathol. 32, 675–679 (2005).

    Article  PubMed  Google Scholar 

  89. Zylka, M.J., Rice, F.L. & Anderson, D.J. Topographically distinct epidermal nociceptive circuits revealed by axonal tracers targeted to mrgprd. Neuron 45, 17–25 (2005).

    Article  CAS  PubMed  Google Scholar 

  90. Brownell, I., Guevara, E., Bai, C.B., Loomis, C.A. & Joyner, A.L. Nerve-derived sonic hedgehog defines a niche for hair follicle stem cells capable of becoming epidermal stem cells. Cell Stem Cell 8, 552–565 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Li, L. et al. The functional organization of cutaneous low-threshold mechanosensory neurons. Cell 147, 1615–1627 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Peters, E.M.J. et al. Developmental timing of hair follicle and dorsal skin innervation in mice. J. Comp. Neurol. 448, 28–52 (2002).

    Article  PubMed  Google Scholar 

  93. Salzberg, Y. et al. Skin-derived cues control arborization of sensory dendrites in Caenorhabditis elegans. Cell 155, 308–320 (2013).

    Article  CAS  PubMed  Google Scholar 

  94. Honig, M.G., Camilli, S.J., Surineni, K.M., Knight, B.K. & Hardin, H.M. The contributions of BMP4, positive guidance cues, and repulsive molecules to cutaneous nerve formation in the chick hindlimb. Dev. Biol. 282, 257–273 (2005).

    Article  CAS  PubMed  Google Scholar 

  95. Peters, E.M.J., Arck, P.C. & Paus, R. Hair growth inhibition by psychoemotional stress: a mouse model for neural mechanisms in hair growth control. Exp. Dermatol. 15, 1–13 (2006).

    Article  CAS  PubMed  Google Scholar 

  96. Xiao, Y. et al. Perivascular hair follicle stem cells associate with a venule annulus. J. Invest. Dermatol. 133, 2324–2331 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Mecklenburg, L. et al. Active hair growth (anagen) is associated with angiogenesis. J. Invest. Dermatol. 114, 909–916 (2000).

    Article  CAS  PubMed  Google Scholar 

  98. Keyes, B.E. et al. Nfatc1 orchestrates aging in hair follicle stem cells. Proc. Natl. Acad. Sci. USA 110, E4950–E4959 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Chen, C.-C. et al. Regenerative hair waves in aging mice and extra-follicular modulators follistatin, Dkk1, and Sfrp4. J. Invest. Dermatol. published online, 10.1038/jid.2014.139 (17 April 2014).

  100. Giangreco, A., Qin, M., Pintar, J.E. & Watt, F.M. Epidermal stem cells are retained in vivo throughout skin aging. Aging Cell 7, 250–259 (2008).

    Article  CAS  PubMed  Google Scholar 

  101. Doles, J., Storer, M., Cozzuto, L., Roma, G. & Keyes, W.M. Age-associated inflammation inhibits epidermal stem cell function. Genes Dev. 26, 2144–2153 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Villeda, S.A. et al. The ageing systemic milieu negatively regulates neurogenesis and cognitive function. Nature 477, 90–94 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Conboy, I.M. et al. Rejuvenation of aged progenitor cells by exposure to a young systemic environment. Nature 433, 760–764 (2005).

    Article  CAS  PubMed  Google Scholar 

  104. Loffredo, F.S. et al. Growth differentiation factor 11 is a circulating factor that reverses age-related cardiac hypertrophy. Cell 153, 828–839 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Gurtner, G.C., Werner, S., Barrandon, Y. & Longaker, M.T. Wound repair and regeneration. Nature 453, 314–321 (2008).

    Article  CAS  PubMed  Google Scholar 

  106. Schmidt, B.A. & Horsley, V. Intradermal adipocytes mediate fibroblast recruitment during skin wound healing. Development 140, 1517–1527 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. 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).

    Article  CAS  PubMed  Google Scholar 

  108. Levy, V., Lindon, C., Zheng, Y., Harfe, B.D. & Morgan, B.A. Epidermal stem cells arise from the hair follicle after wounding. FASEB J. 21, 1358–1366 (2007).

    Article  CAS  PubMed  Google Scholar 

  109. Page, M.E., Lombard, P., Ng, F., Göttgens, B. & Jensen, K.B. The epidermis comprises autonomous compartments maintained by distinct stem cell populations. Cell Stem Cell 13, 471–482 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Langton, A.K., Herrick, S.E. & Headon, D.J. An extended epidermal response heals cutaneous wounds in the absence of a hair follicle stem cell contribution. J. Invest. Dermatol. 128, 1311–1318 (2008).

    Article  CAS  PubMed  Google Scholar 

  111. Epstein, E.H. Basal cell carcinomas: attack of the hedgehog. Nat. Rev. Cancer 8, 743–754 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Ratushny, V., Gober, M.D., Hick, R., Ridky, T.W. & Seykora, J.T. From keratinocyte to cancer: the pathogenesis and modeling of cutaneous squamous cell carcinoma. J. Clin. Invest. 122, 464–472 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Youssef, K.K. et al. Identification of the cell lineage at the origin of basal cell carcinoma. Nat. Cell Biol. 12, 299–305 (2010).

    Article  CAS  PubMed  Google Scholar 

  114. Wang, G.Y., Wang, J., Mancianti, M.-L. & Epstein, E.H. Jr. Basal cell carcinomas arise from hair follicle stem cells in Ptch1+/− mice. Cancer Cell 19, 114–124 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Lapouge, G. et al. Identifying the cellular origin of squamous skin tumors. Proc. Natl. Acad. Sci. USA 108, 7431–7436 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  116. White, A.C. et al. Defining the origins of Ras/p53-mediated squamous cell carcinoma. Proc. Natl. Acad. Sci. USA 108, 7425–7430 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  117. Kasper, M. et al. Wounding enhances epidermal tumorigenesis by recruiting hair follicle keratinocytes. Proc. Natl. Acad. Sci. USA 108, 4099–4104 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  118. Wong, S.Y. & Reiter, J.F. Wounding mobilizes hair follicle stem cells to form tumors. Proc. Natl. Acad. Sci. USA 108, 4093–4098 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  119. Malanchi, I. et al. Cutaneous cancer stem cell maintenance is dependent on |[bgr]|-catenin signalling. Nature 452, 650–653 (2008).

    Article  CAS  PubMed  Google Scholar 

  120. Schober, M. & Fuchs, E. Tumor-initiating stem cells of squamous cell carcinomas and their control by TGF-β and integrin/focal adhesion kinase (FAK) signaling. Proc. Natl. Acad. Sci. USA 108, 10544–10549 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  121. Lapouge, G. et al. Skin squamous cell carcinoma propagating cells increase with tumour progression and invasiveness. EMBO J. 31, 4563–4575 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Driessens, G., Beck, B., Caauwe, A., Simons, B.D. & Blanpain, C. Defining the mode of tumour growth by clonal analysis. Nature 488, 527–530 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Beck, B. et al. A vascular niche and a VEGF-Nrp1 loop regulate the initiation and stemness of skin tumours. Nature 478, 399–403 (2011).

    Article  CAS  PubMed  Google Scholar 

  124. Beronja, S. et al. RNAi screens in mice identify physiological regulators of oncogenic growth. Nature 501, 185–190 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Schramek, D. et al. Direct in vivo RNAi screen unveils myosin IIa as a tumor suppressor of squamous cell carcinomas. Science 343, 309–313 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Green, H., Kehinde, O. & Thomas, J. Growth of cultured human epidermal cells into multiple epithelia suitable for grafting. Proc. Natl. Acad. Sci. USA 76, 5665–5668 (1979).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. O'Connor, N.E., Mulliken, J.B. & Banks-Schlegel, S. Grafting of burns with cultured epithelium prepared from autologous epidermal cells. Lancet 317, 75–78 (1981).

    Article  Google Scholar 

  128. DasGupta, R. & Fuchs, E. Multiple roles for activated LEF/TCF transcription complexes during hair follicle development and differentiation. Development 126, 4557–4568 (1999).

    CAS  PubMed  Google Scholar 

  129. Noramly, S., Freeman, A. & Morgan, B.A. β-catenin signaling can initiate feather bud development. Development 126, 3509–3521 (1999).

    CAS  PubMed  Google Scholar 

  130. Driskell, R.R. et al. Distinct fibroblast lineages determine dermal architecture in skin development and repair. Nature 504, 277–281 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. 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  PubMed  Google Scholar 

  132. Toyoshima, K.-E. et al. Fully functional hair follicle regeneration through the rearrangement of stem cells and their niches. Nat. Commun. 3, 784 (2012).

    Article  CAS  PubMed  Google Scholar 

  133. Lu, C.P. et al. Identification of stem cell populations in sweat glands and ducts reveals roles in homeostasis and wound repair. Cell 150, 136–150 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Goldstein, J. et al. Calcineurin/Nfatc1 signaling links skin stem cell quiescence to hormonal signaling during pregnancy and lactation. Genes Dev. 28, 983–994 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. McGee, H.M. et al. IL-22 promotes fibroblast-mediated wound repair in the skin. J. Invest. Dermatol. 133, 1321–1329 (2013).

    Article  CAS  PubMed  Google Scholar 

  136. Keith, B. & Simon, M.C. Hypoxia-inducible factors, stem cells, and cancer. Cell 129, 465–472 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We are grateful to members of E.F.'s lab, in particular S. Naik, for comments on the manuscript. Y.-C.H. was a New York Stem Cell Foundation Druckenmiller Postdoctoral Fellow and is now supported by US National Institutes of Health Pathway to Independence Award (K99-R00). L.L. is a Helen Hay Whitney Postdoctoral Fellow. E.F. is an Investigator of the Howard Hughes Medical Institute. This work was supported by grants from the US National Institutes of Health, National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01-AR031737 to E.F., R01-AR050452 to E.F. and K99-AR063127 to Y.-C.H.), and by a grant from the Ellison Foundation (E.F.).

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Correspondence to Elaine Fuchs.

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Hsu, YC., Li, L. & Fuchs, E. Emerging interactions between skin stem cells and their niches. Nat Med 20, 847–856 (2014). https://doi.org/10.1038/nm.3643

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