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Local and systemic mechanisms that control the hair follicle stem cell niche

Nature Reviews Molecular Cell Biology volume 25, pages 87–100 (2024)Cite this article

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Abstract

Hair follicles are essential appendages of the mammalian skin, as hair performs vital functions of protection, thermoregulation and sensation. Hair follicles harbour exceptional regenerative abilities as they contain multiple somatic stem cell populations such as hair follicle stem cells (HFSCs) and melanocyte stem cells. Surrounding the stem cells and their progeny, diverse groups of cells and extracellular matrix proteins are organized to form a microenvironment (called ‘niche’) that serves to promote and maintain the optimal functioning of these stem cell populations. Recent studies have shed light on the intricate nature of the HFSC niche and its crucial role in regulating hair follicle regeneration. In this Review, we describe how the niche serves as a signalling hub, communicating, deciphering and integrating both local signals within the skin and systemic inputs from the body and environment to modulate HFSC activity. We delve into the recent advancements in identifying the cellular and molecular nature of the niche, providing a holistic perspective on its essential functions in hair follicle morphogenesis, regeneration and ageing.

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Fig. 1: Establishment of the niche surrounding hair follicle stem cells.
Fig. 2: Temporal and spatial dynamics of local niche controls hair follicle regeneration.
Fig. 3: Systemic regulation of hair follicle stem cells.
Fig. 4: Niche–stem cell crosstalk in stress and ageing.

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References

  1. 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  PubMed  Google Scholar 

  2. Müller-Röver, S. et al. A comprehensive guide for the accurate classification of murine hair follicles in distinct hair cycle stages. J. Invest. Dermatol. 117, 3–15 (2001).

    Article  PubMed  Google Scholar 

  3. 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 

  4. Paus, R. & Cotsarelis, G. The biology of hair follicles. N. Engl. J. Med. 341, 491–497 (1999).

    Article  CAS  PubMed  Google Scholar 

  5. Rendl, M., Polak, L. & Fuchs, E. BMP signaling in dermal papilla cells is required for their hair follicle-inductive properties. Genes Dev. 22, 543–557 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. 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 

  7. Chase, H. B. Growth of the hair. Physiol. Rev. 34, 113–126 (1954).

    Article  CAS  PubMed  Google Scholar 

  8. Craven, A. J. et al. Prolactin delays hair regrowth in mice. J. Endocrinol. 191, 415–425 (2006).

    Article  CAS  PubMed  Google Scholar 

  9. Goldberg, L. J. & Lenzy, Y. Nutrition and hair. Clin. Dermatol. 28, 412–419 (2010).

    Article  PubMed  Google Scholar 

  10. 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 

  11. Shwartz, Y. et al. Cell types promoting goosebumps form a niche to regulate hair follicle stem cells. Cell 182, 578–593.e19 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Zhang, B. et al. Hyperactivation of sympathetic nerves drives depletion of melanocyte stem cells. Nature 577, 676–681 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. 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  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  15. 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 

  16. Claudinot, S., Nicolas, M., Oshima, H., Rochat, A. & Barrandon, Y. Long-term renewal of hair follicles from clonogenic multipotent stem cells. Proc. Natl Acad. Sci. USA 102, 14677–14682 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. 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 

  18. Matsumura, H. et al. Hair follicle aging is driven by transepidermal elimination of stem cells via COL17A1 proteolysis. Science 351, aad4395 (2016).

    Article  PubMed  Google Scholar 

  19. 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 

  20. Driskell, R. R. & Watt, F. M. Understanding fibroblast heterogeneity in the skin. Trends Cell Biol. 25, 92–99 (2015).

    Article  CAS  PubMed  Google Scholar 

  21. 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 

  22. Rahmani, W., Sinha, S. & Biernaskie, J. Immune modulation of hair follicle regeneration. NPJ Regen. Med. 5, 9 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  23. Li, K. N. et al. Skin vasculature and hair follicle cross-talking associated with stem cell activation and tissue homeostasis. eLife 8, e45977 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  24. Heitman, N. et al. Dermal sheath contraction powers stem cell niche relocation during hair cycle regression. Science 367, 161–166 (2020).

    Article  CAS  PubMed  Google Scholar 

  25. Kobielak, K., Pasolli, H. A., Alonso, L., Polak, L. & Fuchs, E. Defining BMP functions in the hair follicle by conditional ablation of BMP receptor IA. J. Cell Biol. 163, 609–623 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Nowak, J. A., Polak, L., Pasolli, H. A. & Fuchs, E. Hair follicle stem cells are specified and function in early skin morphogenesis. Cell Stem Cell 3, 33–43 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Woo, W.-M., Zhen, H. H. & Oro, A. E. Shh maintains dermal papilla identity and hair morphogenesis via a Noggin–Shh regulatory loop. Genes Dev. 26, 1235–1246 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Millar, S. E. Molecular mechanisms regulating hair follicle development. J. Invest. Dermatol. 118, 216–225 (2002).

    Article  CAS  PubMed  Google Scholar 

  29. Sennett, R. & Rendl, M. Mesenchymal–epithelial interactions during hair follicle morphogenesis and cycling. Semin. Cell Dev. Biol. 23, 917–927 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Hardy, M. H. The secret life of the hair follicle. Trends Genet. 8, 55–61 (1992).

    Article  CAS  PubMed  Google Scholar 

  31. Xu, Z. et al. Embryonic attenuated Wnt/β-catenin signaling defines niche location and long-term stem cell fate in hair follicle. eLife 4, e10567 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  32. Saxena, N., Mok, K.-W. & Rendl, M. An updated classification of hair follicle morphogenesis. Exp. Dermatol. 28, 332–344 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  33. Schmidt-Ullrich, R. & Paus, R. Molecular principles of hair follicle induction and morphogenesis. BioEssays 27, 247–261 (2005).

    Article  CAS  PubMed  Google Scholar 

  34. Ouspenskaia, T., Matos, I., Mertz, A. F., Fiore, V. F. & Fuchs, E. WNT-SHH antagonism specifies and expands stem cell prior. to niche formation. Cell 164, 156–169 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Morita, R. et al. Tracing the origin of hair follicle stem cells. Nature 594, 547–552 (2021).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  37. Oliver, R. F. The induction of hair follicle formation in the adult hooded rat by vibrissa dermal papillae. J. Embryol. Exp. Morphol. 23, 219–236 (1970).

    CAS  PubMed  Google Scholar 

  38. Jahoda, Ca. B., Horne, K. A. & Oliver, R. F. Induction of hair growth by implantation of cultured dermal papilla cells. Nature 311, 560–562 (1984).

    Article  CAS  PubMed  Google Scholar 

  39. Paus, R. Principles of hair cycle control. J. Dermatol. 25, 793–802 (1998).

    Article  CAS  PubMed  Google Scholar 

  40. Kobielak, K., Stokes, N., Cruz, J., de la, Polak, L. & Fuchs, E. Loss of a quiescent niche but not follicle stem cells in the absence of bone morphogenetic protein signaling. Proc. Natl Acad. Sci. USA 104, 10063–10068 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. 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 

  42. Horsley, V., Aliprantis, A. O., Polak, L., Glimcher, L. H. & Fuchs, E. NFATc1 balances quiescence and proliferation of skin stem. Cells Cell 132, 299–310 (2008).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Morgan, B. A. The dermal papilla: an instructive niche for epithelial stem and progenitor cells in development and regeneration of the hair follicle. Cold Spring Harb. Perspect. Med. 4, a015180 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  45. 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 

  46. Foitzik, K. et al. Control of murine hair follicle regression (catagen) by TGF-β1 in vivo. FASEB J. 14, 752–760 (2000).

    Article  CAS  PubMed  Google Scholar 

  47. Mesa, K. R. et al. Niche-induced cell death and epithelial phagocytosis regulate hair follicle stem cell pool. Nature 522, 94–97 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Harshuk-Shabso, S., Dressler, H., Niehrs, C., Aamar, E. & Enshell-Seijffers, D. Fgf and Wnt signaling interaction in the mesenchymal niche regulates the murine hair cycle clock. Nat. Commun. 11, 5114 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Rahmani, W. et al. Hair follicle dermal stem cells regenerate the dermal sheath, repopulate the dermal papilla, and modulate hair type. Dev. Cell 31, 543–558 (2014).

    Article  CAS  PubMed  Google Scholar 

  50. Martino, P. A., Heitman, N. & Rendl, M. The dermal sheath: an emerging component of the hair follicle stem cell niche. Exp. Dermatol. 30, 512–521 (2021).

    Article  PubMed  Google Scholar 

  51. Martino, P. et al. Progenitor-derived endothelin controls dermal sheath contraction for hair follicle regression. Nat. Cell Biol. 25, 222–234 (2023).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Rodeheffer, M. S., Birsoy, K. & Friedman, J. M. Identification of white adipocyte progenitor cell vivo. Cell 135, 240–249 (2008).

    Article  CAS  PubMed  Google Scholar 

  53. Cristancho, A. G. & Lazar, M. A. Forming functional fat: a growing understanding of adipocyte differentiation. Nat. Rev. Mol. Cell Biol. 12, 722–734 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Rivera-Gonzalez, G. C. et al. Skin adipocyte stem cell self-renewal is regulated by a PDGFA/AKT-signaling axis. Cell Stem Cell 19, 738–751 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. 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 

  56. 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 

  57. Zhang, B. & Hsu, Y.-C. Emerging roles of transit-amplifying cells in tissue regeneration and cancer. Wiley Interdiscip. Rev. Dev. Biol. 6, 10.1002/wdev.282 (2017).

    Article  PubMed Central  Google Scholar 

  58. Kimura-Ueki, M. et al. Hair cycle resting phase is regulated by cyclic epithelial FGF18 signaling. J. Invest. Dermatol. 132, 1338–1345 (2012).

    Article  CAS  PubMed  Google Scholar 

  59. Perdigoto, C. N. et al. Polycomb-mediated repression and sonic hedgehog signaling interact to regulate merkel cell specification during skin development. PLoS Genet. 12, e1006151 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  60. 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 

  61. Botchkarev, V. A., Botchkareva, N. V., Peters, E. M. & Paus, R. Epithelial growth control by neurotrophins: leads and lessons from the hair follicle. Prog. Brain Res. 146, 493–513 (2004).

    Article  CAS  PubMed  Google Scholar 

  62. Rutlin, M. et al. The cellular and molecular basis of direction selectivity of Aδ-LTMRs. Cell 159, 1640–1651 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Cheng, C.-C. et al. Hair follicle epidermal stem cells define a niche for tactile sensation. eLife 7, e3883 (2018).

    Article  Google Scholar 

  64. Peng, J., Chen, H. & Zhang, B. Nerve–stem cell crosstalk in skin regeneration and diseases. Trends Mol. Med. 28, 583–595 (2022).

    Article  CAS  PubMed  Google Scholar 

  65. Li, K. N. & Tumbar, T. Hair follicle stem cells as a skin-organizing signaling center during adult homeostasis. EMBO J. 40, e107135 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Zhang, B. et al. Hair follicles’ transit-amplifying cells govern concurrent dermal adipocyte production through Sonic Hedgehog. Genes. Dev. 30, 2325–2338 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Durward, A. & Rudall, K. M. in The Biology of Hair Growth (eds Montagna, W. & Ellis, R. A.) ch. 9 189–218 (Academic Press, 1958).

  68. Moretti, G., Ellis, R. A. & Mescon, H. Vascular patterns in the skin of the face. J. Invest. Dermatol. 33, 103–112 (1959).

    Article  CAS  PubMed  Google Scholar 

  69. Skobe, M. & Detmar, M. Structure, function, and molecular control of the skin lymphatic system. J. Investig. Dermatol. Symp. Proc. 5, 14–19 (2000).

    Article  CAS  PubMed  Google Scholar 

  70. Kam, C. Y. et al. Mechanisms of skin vascular maturation and maintenance captured by longitudinal imaging of live mice. Cell 186, 2345–2360.e16 (2023).

    Article  CAS  PubMed  Google Scholar 

  71. Li, K. N., Chovatiya, G., Ko, D. Y., Sureshbabu, S. & Tumbar, T. Blood endothelial ALK1–BMP4 signaling axis regulates adult hair follicle stem cell activation. EMBO J. 42, e112196 (2023).

    Article  CAS  PubMed  Google Scholar 

  72. Braverman, I. M. Ultrastructure and organization of the cutaneous microvasculature in normal and pathologic states. J. Invest. Dermatol. 93, S2–S9 (1989).

    Article  Google Scholar 

  73. Gay, D. & Ito, M. The seed tends to the soil: hair follicle stem cells remodel their lymphatic niche. Cell Stem Cell 25, 733–734 (2019).

    Article  CAS  PubMed  Google Scholar 

  74. Peña-Jimenez, D. et al. Lymphatic vessels interact dynamically with the hair follicle stem cell niche during skin regeneration in vivo. EMBO J. 38, e101688 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  75. Gur-Cohen, S. et al. Stem cell-driven lymphatic remodeling coordinates tissue regeneration. Science 366, 1218–1225 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Di Meglio, P., Perera, G. K. & Nestle, F. O. The multitasking organ: recent insights into skin immune function. Immunity 35, 857–869 (2011).

    Article  PubMed  Google Scholar 

  77. Quaresma, J. A. S. Organization of the skin immune system and compartmentalized immune responses in infectious diseases. Clin. Microbiol. Rev. 32, e00034-18 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  78. Lay, K. et al. Stem cells repurpose proliferation to contain a breach in their niche barrier. eLife 7, e41661 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  79. Paus, R., Nickoloff, B. J. & Ito, T. A ‘hairy’ privilege. Trends Immunol. 26, 32–40 (2005).

    Article  CAS  PubMed  Google Scholar 

  80. Castellana, D., Paus, R. & Perez-Moreno, M. Macrophages contribute to the cyclic activation of adult hair follicle stem cells. PLOS Biol. 12, e1002002 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  81. Wang, E. C. E., Dai, Z., Ferrante, A. W., Drake, C. G. & Christiano, A. M. A subset of TREM2+ dermal macrophages secretes oncostatin M to maintain hair follicle stem cell quiescence and inhibit hair growth. Cell Stem Cell 24, 654–669.e6 (2019).

    Article  CAS  PubMed  Google Scholar 

  82. Ali, N. et al. Regulatory T cells in skin facilitate epithelial stem cell differentiation. Cell 169, 1119–1129.e11 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Ali, N. & Rosenblum, M. D. Regulatory T cells in skin. Immunology 152, 372–381 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Fraser, A. S., Nay, T. & Turner, H. N. Growth of the mouse coat. II. Effect of sex and pregnancy. Aust. J. Biol. Sci. 6, 645–656 (1953).

    Article  CAS  PubMed  Google Scholar 

  85. Movérare, S., Lindberg, M. K., Ohlsson, C., Faergemann, J. & Gustafsson, J.-Å. Estrogen receptor α, but not estrogen receptor β, is involved in the regulation of the hair follicle cycling as well as the thickness of epidermis in male mice. J. Invest. Dermatol. 119, 1053–1058 (2002).

    Article  PubMed  Google Scholar 

  86. Osthaus, B. et al. Hair coat properties of donkeys, mules and horses in a temperate climate. Equine Vet. J. 50, 339–342 (2018).

    Article  CAS  PubMed  Google Scholar 

  87. Ferreira, M. S. et al. Transcriptomic regulation of seasonal coat color change in hares. Ecol. Evol. 10, 1180–1192 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  88. O’Brien, C., Darcy-Dunne, M. R. & Murphy, B. A. The effects of extended photoperiod and warmth on hair growth in ponies and horses at different times of year. PLoS ONE 15, e0227115 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  89. Tietgen, L. et al. Fur colour in the Arctic fox: genetic architecture and consequences for fitness. Proc. R. Soc. B Biol. Sci. 288, 20211452 (2021).

    Article  CAS  Google Scholar 

  90. Roman, K., Wilk, M., Książek, P., Czyż, K. & Roman, A. the effect of the season, the maintenance system and the addition of polyunsaturated fatty acids on selected biological and physicochemical features of rabbit fur. Animals 12, 971 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  91. Aragona, M. et al. Mechanisms of stretch-mediated skin expansion at single-cell resolution. Nature 584, 268–273 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Xie, Y. et al. Hair shaft miniaturization causes stem cell depletion through mechanosensory signals mediated by a Piezo1-calcium-TNF-α axis. Cell Stem Cell 29, 70–85.e6 (2022).

    Article  CAS  PubMed  Google Scholar 

  93. Cotsarelis, G. & Millar, S. E. Towards a molecular understanding of hair loss and its treatment. Trends Mol. Med. 7, 293–301 (2001).

    Article  CAS  PubMed  Google Scholar 

  94. Lei, M. & Chuong, C.-M. Aging, alopecia, and stem cells. Science 351, 559–560 (2016).

    Article  CAS  PubMed  Google Scholar 

  95. Meacham, C. E., DeVilbiss, A. W. & Morrison, S. J. Metabolic regulation of somatic stem cells in vivo. Nat. Rev. Mol. Cell Biol. 23, 428–443 (2022).

    Article  CAS  PubMed  Google Scholar 

  96. Flores, A. et al. Lactate dehydrogenase activity drives hair follicle stem cell activation. Nat. Cell Biol. 19, 1017–1026 (2017).

    Article  CAS  PubMed  Google Scholar 

  97. Kim, C. S. et al. Glutamine metabolism controls stem cell fate reversibility and long-term maintenance in the hair follicle. Cell Metab. 32, 629–642.e8 (2020).

    Article  CAS  PubMed  Google Scholar 

  98. Karnik, P. et al. Hair follicle stem cell-specific PPARγ deletion causes scarring alopecia. J. Invest. Dermatol. 129, 1243–1257 (2009).

    Article  CAS  PubMed  Google Scholar 

  99. Deng, Z. et al. mTOR signaling promotes stem cell activation via counterbalancing BMP-mediated suppression during hair regeneration. J. Mol. Cell Biol. 7, 62–72 (2015).

    Article  CAS  PubMed  Google Scholar 

  100. Shapiro, J. Hair loss in women. N. Engl. J. Med. 357, 1620–1630 (2007).

    Article  CAS  PubMed  Google Scholar 

  101. Strumia, R. Eating disorders and the skin. Clin. Dermatol. 31, 80–85 (2013).

    Article  PubMed  Google Scholar 

  102. Guo, E. L. & Katta, R. Diet and hair loss: effects of nutrient deficiency and supplement use. Dermatol. Pract. Concept. 7, 1–10 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  103. Morinaga, H. et al. Obesity accelerates hair thinning by stem cell-centric converging mechanisms. Nature 595, 266–271 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Paatela, E., Munson, D. & Kikyo, N. Circadian regulation in tissue regeneration. Int. J. Mol. Sci. 20, 2263 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Ruby, C. L., Major, R. J. & Hinrichsen, R. D. Regulation of tissue regeneration by the circadian clock. Eur. J. Neurosci. 53, 3576–3597 (2021).

    Article  CAS  PubMed  Google Scholar 

  106. Tanioka, M. et al. Molecular clocks in mouse skin. J. Invest. Dermatol. 129, 1225–1231 (2009).

    Article  CAS  PubMed  Google Scholar 

  107. Akashi, M. et al. Noninvasive method for assessing the human circadian clock using hair follicle cells. Proc. Natl Acad. Sci. USA 107, 15643–15648 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Al-Nuaimi, Y. et al. A meeting of two chronobiological systems: circadian proteins period1 and BMAL1 modulate the human hair cycle clock. J. Invest. Dermatol. 134, 610–619 (2014).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  PubMed  PubMed Central  Google Scholar 

  111. 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  CAS  PubMed  PubMed Central  Google Scholar 

  112. 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  CAS  PubMed  PubMed Central  Google Scholar 

  113. COMAISH, S. Autoradiographic studies of hair groawth in various dermatoses: investigation of a possible circadian rhythm in human hair growth. Br. J. Dermatol. 81, 283–288 (1969).

    Article  CAS  PubMed  Google Scholar 

  114. Roosterman, D., Goerge, T., Schneider, S. W., Bunnett, N. W. & Steinhoff, M. Neuronal control of skin function: the skin as a neuroimmunoendocrine organ. Physiol. Rev. 86, 1309–1379 (2006).

    Article  CAS  PubMed  Google Scholar 

  115. Glatte, P., Buchmann, S. J., Hijazi, M. M., Illigens, B. M.-W. & Siepmann, T. Architecture of the cutaneous autonomic nervous system. Front. Neurol. 10, 970 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  116. 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 

  117. Bai, L. et al. Genetic identification of an expansive mechanoreceptor sensitive to skin stroking. Cell 163, 1783–1795 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Furlan, A. et al. Visceral motor neuron diversity delineates a cellular basis for nipple- and pilo-erection muscle control. Nat. Neurosci. 19, 1331–1340 (2016).

    Article  CAS  PubMed  Google Scholar 

  119. 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 

  120. Fan, S. M.-Y. et al. External light activates hair follicle stem cells through eyes via an ipRGC–SCN–sympathetic neural pathway. Proc. Natl Acad. Sci. USA 115, E6880–E6889 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Brunet, A., Goodell, M. A. & Rando, T. A. Ageing and rejuvenation of tissue stem cells and their niches. Nat. Rev. Mol. Cell Biol. 24, 45–62 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  122. Ogrodnik, M. & Gladyshev, V. N. The meaning of adaptation in aging: insights from cellular senescence, epigenetic clocks and stem cell alterations. Nat. Aging 3, 766–775 (2023).

    Article  CAS  PubMed  Google Scholar 

  123. Colavincenzo, M. L. & Granstein, R. D. Stress and the skin: a meeting report of the weill cornell symposium on the science of dermatology. J. Invest. Dermatol. 126, 2560–2561 (2006).

    Article  CAS  PubMed  Google Scholar 

  124. Sawaya, M. E. & Hordinsky, M. K. glucocorticoid regulation of hair growth in alopecia areata. J. Invest. Dermatol. 104, 30 (1995).

    Article  Google Scholar 

  125. Jang, H., Jo, Y., Lee, J. H. & Choi, S. Aging of hair follicle stem cells and their niches. BMB Rep. 56, 2–9 (2023).

    Article  CAS  PubMed  Google Scholar 

  126. Steptoe, A. & Kivimäki, M. Stress and cardiovascular disease. Nat. Rev. Cardiol. 9, 360–370 (2012).

    Article  CAS  PubMed  Google Scholar 

  127. Qin, H.-Y., Cheng, C.-W., Tang, X.-D. & Bian, Z.-X. Impact of psychological stress on irritable bowel syndrome. World J. Gastroenterol. 20, 14126–14131 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  128. Rosenberg, S. L., Miller, G. E., Brehm, J. M. & Celedón, J. C. Stress and asthma: novel insights on genetic, epigenetic and immunologic mechanisms. J. Allergy Clin. Immunol. 134, 1009–1015 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Navarini, A. A. & Nobbe, S. Marie Antoinette syndrome. Arch. Dermatol. 145, 656–656 (2009).

    Article  PubMed  Google Scholar 

  130. Arck, P. C., Slominski, A., Theoharides, T. C., Peters, E. M. J. & Paus, R. Neuroimmunology of stress: skin takes center stage. J. Invest. Dermatol. 126, 1697–1704 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Condamina, M. et al. Factors associated with perceived stress in patients with vitiligo in the ComPaRe e-cohort. J. Am. Acad. Dermatol. 86, 696–698 (2022).

    Article  PubMed  Google Scholar 

  132. Choi, S. et al. Corticosterone inhibits GAS6 to govern hair follicle stem-cell quiescence. Nature 592, 428–432 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. 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 

  134. Rachmin, I. et al. Stress-associated ectopic differentiation of melanocyte stem cells and ORS amelanotic melanocytes in an ex vivo human hair follicle model. Exp. Dermatol. 30, 578–587 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Lerner, A. B. Gray hair and sympathectomy. Report of a case. Arch. Dermatol. 93, 235–236 (1966).

    Article  CAS  PubMed  Google Scholar 

  136. Ortonne, J. P., Thivolet, J. & Guillet, R. Graying of hair with age and sympathectomy. Arch. Dermatol. 118, 876–877 (1982).

    Article  CAS  PubMed  Google Scholar 

  137. Fernandez-Flores, A., Saeb-Lima, M. & Cassarino, D. S. Histopathology of aging of the hair follicle. J. Cutan. Pathol. 46, 508–519 (2019).

    Article  PubMed  Google Scholar 

  138. Williams, R., Pawlus, A. D. & Thornton, M. J. Getting under the skin of hair aging: the impact of the hair follicle environment. Exp. Dermatol. 29, 588–597 (2020).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  140. Keyes, B. E. & Fuchs, E. Stem cells: aging and transcriptional fingerprints. J. Cell Biol. 217, 79–92 (2017).

    Article  PubMed  Google Scholar 

  141. Zhang, S. & Duan, E. Fighting against skin aging. Cell Transpl. 27, 729–738 (2018).

    Article  Google Scholar 

  142. 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 

  143. Ge, Y. et al. The aging skin microenvironment dictates stem cell behavior. Proc. Natl Acad. Sci. USA 117, 5339–5350 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Zhang, C. et al. Escape of hair follicle stem cells causes stem cell exhaustion during aging. Nat. Aging 1, 889–903 (2021).

    Article  PubMed  Google Scholar 

  145. Lay, K., Kume, T. & Fuchs, E. FOXC1 maintains the hair follicle stem cell niche and governs stem cell quiescence to preserve long-term tissue-regenerating potential. Proc. Natl Acad. Sci. USA 113, E1506–E1515 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Li, G. et al. SIRT7 activates quiescent hair follicle stem cells to ensure hair growth in mice. EMBO J. 39, e104365 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Barrandon, Y. & Green, H. Three clonal types of keratinocyte with different capacities for multiplication. Proc. Natl Acad. Sci. USA 84, 2302–2306 (1987).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Koester, J. et al. Niche stiffening compromises hair follicle stem cell potential during ageing by reducing bivalent promoter accessibility. Nat. Cell Biol. 23, 771–781 (2021).

    Article  CAS  PubMed  Google Scholar 

  149. Branchet, M. C., Boisnic, S., Frances, C., Lesty, C. & Robert, L. Morphometric analysis of dermal collagen fibers in normal human skin as a function of age. Arch. Gerontol. Geriatr. 13, 1–14 (1991).

    Article  CAS  PubMed  Google Scholar 

  150. Farage, M. A., Miller, K. W., Elsner, P. & Maibach, H. I. Characteristics of the aging skin. Adv. Wound Care 2, 5–10 (2013).

    Article  Google Scholar 

  151. Duncan, K. O. & Leffell, D. J. Preoperative assessment of the elderly patient. Dermatol. Clin. 15, 583–593 (1997).

    Article  CAS  PubMed  Google Scholar 

  152. Salzer, M. C. et al. Identity noise and adipogenic traits characterize dermal fibroblast aging. Cell 175, 1575–1590.e22 (2018).

    Article  CAS  PubMed  Google Scholar 

  153. Mine, S., Fortunel, N. O., Pageon, H. & Asselineau, D. Aging alters functionally human dermal papillary fibroblasts but not reticular fibroblasts: a new view of skin morphogenesis and aging. PLoS ONE 3, e4066 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  154. Shin, W. et al. Dysfunction of hair follicle mesenchymal progenitors contributes to age-associated hair loss. Dev. Cell 53, 185–198.e7 (2020).

    Article  CAS  PubMed  Google Scholar 

  155. Rodriguez, R. S. et al. Memory regulatory T cells reside in human skin. J. Clin. Invest. 124, 1027–1036 (2014).

    Article  CAS  Google Scholar 

  156. Liu, Z. et al. Glucocorticoid signaling and regulatory T cells cooperate to maintain the hair-follicle stem-cell niche. Nat. Immunol. 23, 1086–1097 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. 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 

  158. 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 

  159. Lu, Z. et al. Hair follicle stem cells regulate retinoid metabolism to maintain the self-renewal niche for melanocyte stem cells. eLife 9, e52712 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Sun, Q. et al. Dedifferentiation maintains melanocyte stem cells in a dynamic niche. Nature 616, 774–782 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. 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 

  162. Geueke, A. et al. The anti-apoptotic Bcl-2 protein regulates hair follicle stem cell function. EMBO Rep. 22, e52301 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. Rognoni, E. & Watt, F. M. Skin cell heterogeneity in development, wound healing, and cancer. Trends Cell Biol. 28, 709–722 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  165. Sen, C. K. et al. Human skin wounds: a major and snowballing threat to public health and the economy. Wound Repair. Regen. 17, 763–771 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  167. Plikus, M. V. et al. Regeneration of fat cells from myofibroblasts during wound healing. Science 355, 748–752 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. Rinkevich, Y. et al. Identification and isolation of a dermal lineage with intrinsic fibrogenic potential. Science 348, aaa2151 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  169. Jiang, D. et al. Two succeeding fibroblastic lineages drive dermal development and the transition from regeneration to scarring. Nat. Cell Biol. 20, 422–431 (2018).

    Article  CAS  PubMed  Google Scholar 

  170. Correa-Gallegos, D. et al. Patch repair of deep wounds by mobilized fascia. Nature 576, 287–292 (2019).

    Article  CAS  PubMed  Google Scholar 

  171. Guerrero-Juarez, C. F. et al. Single-cell analysis reveals fibroblast heterogeneity and myeloid-derived adipocyte progenitors in murine skin wounds. Nat. Commun. 10, 650 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  172. Mascharak, S. et al. Preventing Engrailed-1 activation in fibroblasts yields wound regeneration without scarring. Science 372, eaba2374 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  173. Wang, Q. et al. A multi-scale model for hair follicles reveals heterogeneous domains driving rapid spatiotemporal hair growth patterning. eLife 6, e22772 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  174. Yu, Z. et al. Hoxc-dependent mesenchymal niche heterogeneity drives regional hair follicle regeneration. Cell Stem Cell 23, 487–500.e6 (2018).

    Article  CAS  PubMed  Google Scholar 

  175. Chang, H. Y. et al. Diversity, topographic differentiation, and positional memory in human fibroblasts. Proc. Natl Acad. Sci. USA 99, 12877–12882 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  176. Xu, Z. et al. Anatomically distinct fibroblast subsets determine skin autoimmune patterns. Nature 601, 118–124 (2022).

    Article  CAS  PubMed  Google Scholar 

  177. Picardo, M. et al. Vitiligo. Nat. Rev. Dis. Prim. 1, 15011 (2015).

    Article  PubMed  Google Scholar 

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Acknowledgements

The authors thank Y.-C. Hsu, J. Peng, C. Wang and P. Zhang for discussion and critical feedback of the manuscript; J. Peng for designing the illustrations and Y. Xie for help with the revision. The authors regret that they were not able to discuss all the relevant works here owing to space constraints. This work was supported in part by grants from the National Natural Science Foundation of China (Project 32170850 to B.Z., Projects 32070873 and 32225018 to T.C.), Ministry of Science and Technology of China (Projects 2021YFA1101000 and 2022YFA0807300 to T.C.), Westlake University Education Foundation and Westlake Laboratory of Life Sciences and Biomedicine.

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  1. School of Life Sciences, Westlake University, Hangzhou, Zhejiang, China

    Bing Zhang

  2. Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, Zhejiang, China

    Bing Zhang

  3. National Institute of Biological Sciences, Beijing, China

    Ting Chen

  4. Tsinghua Institute of Multidisciplinary Biomedical Research, Tsinghua University, Beijing, China

    Ting Chen

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Zhang, B., Chen, T. Local and systemic mechanisms that control the hair follicle stem cell niche. Nat Rev Mol Cell Biol 25, 87–100 (2024). https://doi.org/10.1038/s41580-023-00662-3

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