Skip to main content
SpringerLink
Log in
Book cover

Tissue-Specific Stem Cell Niche pp 1–26Cite as

The Hair Follicle Stem Cell Niche: The Bulge and Its Environment

  • Chapter
  • First Online:

  • 1401 Accesses

Part of the book series: Stem Cell Biology and Regenerative Medicine ((STEMCELL))

Abstract

The hair follicle (HF) is a dynamic miniorgan that has become one of the best understood models of tissue stem cell (SC) behavior. Distinct temporal orchestration of HF SC self-renewal, differentiation, and quiescence makes the HF an ideal system for studying regulation in a SC niche during normal homeostasis of a tissue. The HF bulge structure acts as the SCs' maintenance niche, and houses a heterogeneous collection of SCs that promote HF growth and contribute to epidermal wound repair. Bulge-neighboring cells contribute to the niche environment and are important for regulating HFSC activation, quiescence and differentiation. This review will explore the HFSC behavior within their niche, and the mechanisms that contribute to the homeostasis and maintenance of HFSCs in adult skin.

This is a preview of subscription content, log in via an institution.

Chapter
USD   29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD   129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD   169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD   169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Learn about institutional subscriptions

Abbreviations

ASK1:

Apoptosis signal-regulating kinase 1

BCC:

Basal cell carcinoma

Bmp:

Bone morphogenic protein

BrdU:

Bromodeoxyuridine

CDKI:

Cyclin-dependent kinase inhibitor

DMBA:

9,10-dimethyl-1,2-benzanthracene

DP:

Dermal papilla

FACS:

Fluorescence-activated cell sorting

Fgf:

Fibroblast growth factor

GFP:

Green fluorescent protein

H2B:

Histone 2B

HF:

Hair follicle

HH:

Hedgehog

3HTdR:

Tritiated thymidine

iDTR:

Inducible diphtheria toxin receptor

IRS:

Inner root sheath

K:

Keratin

ORS:

Outer root sheath

Lgr5:

Leucine rich repeat containing G protein coupled receptor 5

LRC:

Label retaining cell

MAP3K:

Mitogen-activated protein kinase kinase kinase

MHC:

Major histocompatibility complex

MSC:

Melanocyte stem cell

NFATc1:

Nuclear factor of activated T cells, cytoplasmic, calcineurin dependent 1

NSC:

Neural stem cell

ROS:

Reactive oxygen species

Runx1:

Runt-related transcription factor 1

SC:

Stem cell

SCC:

Squamous cell carcinoma

SG:

Sebaceous gland

Shh:

Sonic hedgehog

TGF-β:

Transforming growth factor, beta

TPA:

12-O- tetradecanoylphorbol-13-acetate

VEGF:

Vascular endothelial growth factor

Wnt:

Wingless-type MMTV integration site family

References

  1. Muller-Rover S, Handjiski B, van der Veen C, Eichmuller S, Foitzik K, McKay IA, et al. A comprehensive guide for the accurate classification of murine hair follicles in distinct hair cycle stages. J Invest Dermatol. 2001;117(1):3–15. doi:10.1046/j.0022-202x.2001.01377.x.

    Article  CAS  PubMed  Google Scholar 

  2. Waghmare SK, Bansal R, Lee J, Zhang YV, McDermitt DJ, Tumbar T. Quantitative proliferation dynamics and random chromosome segregation of hair follicle stem cells. EMBO J. 2008;27(9):1309–20. doi:10.1038/emboj.2008.72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Zhang YV, Cheong J, Ciapurin N, McDermitt DJ, Tumbar T. Distinct self-renewal and differentiation phases in the niche of infrequently dividing hair follicle stem cells. Cell Stem Cell. 2009;5(3):267–78. doi:10.1016/j.stem.2009.06.004.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Cotsarelis G. Epithelial stem cells: a folliculocentric view. J Invest Dermatol. 2006;126(7):1459–68. doi:10.1038/sj.jid.5700376.

    Article  CAS  PubMed  Google Scholar 

  5. Fuchs E. Scratching the surface of skin development. Nature. 2007;445(7130):834–42. doi:10.1038/nature05659.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Rompolas P, Greco V. Stem cell dynamics in the hair follicle niche. Semin Cell Dev Biol. 2014;25–26:34–42. doi:10.1016/j.semcdb.2013.12.005.

    Article  PubMed  Google Scholar 

  7. Yang CC, Cotsarelis G. Review of hair follicle dermal cells. J Dermatol Sci. 2010;57(1):2–11. doi:10.1016/j.jdermsci.2009.11.005.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Sennett R, Rendl M. Mesenchymal-epithelial interactions during hair follicle morphogenesis and cycling. Semin Cell Dev Biol. 2012;23(8):917–27. doi:10.1016/j.semcdb.2012.08.011.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Goldstein J, Horsley V. Home sweet home: skin stem cell niches. Cell Mol Life Sci. 2012;69(15):2573–82. doi:10.1007/s00018-012-0943-3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Cotsarelis G, Sun TT, Lavker RM. Label-retaining cells reside in the bulge area of pilosebaceous unit: implications for follicular stem cells, hair cycle, and skin carcinogenesis. Cell. 1990;61(7):1329–37.

    Article  CAS  PubMed  Google Scholar 

  11. Oshima H, Rochat A, Kedzia C, Kobayashi K, Barrandon Y. Morphogenesis and renewal of hair follicles from adult multipotent stem cells. Cell. 2001;104(2):233–45.

    Article  CAS  PubMed  Google Scholar 

  12. 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. 2005;102(41):14677–82. doi:10.1073/pnas.0507250102.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Tumbar T, Guasch G, Greco V, Blanpain C, Lowry WE, Rendl M, et al. Defining the epithelial stem cell niche in skin. Science. 2004;303(5656):359–63. doi:10.1126/science.1092436.

    Article  CAS  PubMed  Google Scholar 

  14. Trempus CS, Morris RJ, Bortner CD, Cotsarelis G, Faircloth RS, Reece JM, et al. Enrichment for living murine keratinocytes from the hair follicle bulge with the cell surface marker CD34. J Invest Dermatol. 2003;120(4):501–11. doi:10.1046/j.1523-1747.2003.12088.x.

    Article  CAS  PubMed  Google Scholar 

  15. Lyle S, Christofidou-Solomidou M, Liu Y, Elder DE, Albelda S, Cotsarelis G. The C8/144B monoclonal antibody recognizes cytokeratin 15 and defines the location of human hair follicle stem cells. J Cell Sci. 1998;111(Pt 21):3179–88.

    CAS  PubMed  Google Scholar 

  16. Morris RJ, Liu Y, Marles L, Yang Z, Trempus C, Li S, et al. Capturing and profiling adult hair follicle stem cells. Nat Biotechnol. 2004;22(4):411–7. doi:10.1038/nbt950.

    Article  CAS  PubMed  Google Scholar 

  17. Lee J, Tumbar T. Hairy tale of signaling in hair follicle development and cycling. Semin Cell Dev Biol. 2012;23(8):906–16. doi:10.1016/j.semcdb.2012.08.003.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Hsu YC, Pasolli HA, Fuchs E. Dynamics between stem cells, niche, and progeny in the hair follicle. Cell. 2011;144(1):92–105. doi:10.1016/j.cell.2010.11.049.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Fuchs E. The tortoise and the hair: slow-cycling cells in the stem cell race. Cell. 2009;137(5):811–9. doi:10.1016/j.cell.2009.05.002.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Li L, Clevers H. Coexistence of quiescent and active adult stem cells in mammals. Science. 2010;327(5965):542–5. doi:10.1126/science.1180794.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Plikus MV, Mayer JA, de la Cruz D, Baker RE, Maini PK, Maxson R, et al. Cyclic dermal BMP signalling regulates stem cell activation during hair regeneration. Nature. 2008;451(7176):340–4. doi:10.1038/nature06457.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Kobielak K, Stokes N, de la Cruz J, 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. 2007;104(24):10063–8. doi:10.1073/pnas.0703004104.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Horsley V, Aliprantis AO, Polak L, Glimcher LH, Fuchs E. NFATc1 balances quiescence and proliferation of skin stem cells. Cell. 2008;132(2):299–310. doi:10.1016/j.cell.2007.11.047.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Takeda N, Jain R, Leboeuf MR, Padmanabhan A, Wang Q, Li L, et al. Hopx expression defines a subset of multipotent hair follicle stem cells and a progenitor population primed to give rise to K6+ niche cells. Development. 2013;140(8):1655–64. doi:10.1242/dev.093005.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Castilho RM, Squarize CH, Chodosh LA, Williams BO, Gutkind JS. mTOR mediates Wnt-induced epidermal stem cell exhaustion and aging. Cell Stem Cell. 2009;5(3):279–89. doi:10.1016/j.stem.2009.06.017.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Nakajima T, Inui S, Fushimi T, Noguchi F, Kitagawa Y, Reddy JK, et al. Roles of MED1 in quiescence of hair follicle stem cells and maintenance of normal hair cycling. J Invest Dermatol. 2013;133(2):354–60. doi:10.1038/jid.2012.293.

    Article  CAS  PubMed  Google Scholar 

  27. Chen T, Heller E, Beronja S, Oshimori N, Stokes N, Fuchs E. An RNA interference screen uncovers a new molecule in stem cell self-renewal and long-term regeneration. Nature. 2012;485(7396):104–8. doi:10.1038/nature10940.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Blanpain C, Lowry WE, Geoghegan A, Polak L, Fuchs E. Self-renewal, multipotency, and the existence of two cell populations within an epithelial stem cell niche. Cell. 2004;118(5):635–48. doi:10.1016/j.cell.2004.08.012.

    Article  CAS  PubMed  Google Scholar 

  29. Lee J, Hoi CS, Lilja KC, White BS, Lee SE, Shalloway D, et al. Runx1 and p21 synergistically limit the extent of hair follicle stem cell quiescence in vivo. Proc Natl Acad Sci USA. 2013;110(12):4634–9. doi:10.1073/pnas.1213015110.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Osorio KM, Lee SE, McDermitt DJ, Waghmare SK, Zhang YV, Woo HN, et al. Runx1 modulates developmental, but not injury-driven, hair follicle stem cell activation. Development. 2008;135(6):1059–68. doi:10.1242/dev.012799.

    Article  CAS  PubMed  Google Scholar 

  31. Hoi CS, Lee SE, Lu SY, McDermitt DJ, Osorio KM, Piskun CM, et al. Runx1 directly promotes proliferation of hair follicle stem cells and epithelial tumor formation in mouse skin. Mol Cell Biol. 2010;30(10):2518–36. doi:10.1128/MCB.01308-09.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Devgan V, Mammucari C, Millar SE, Brisken C, Dotto GP. p21WAF1/Cip1 is a negative transcriptional regulator of Wnt4 expression downstream of Notch1 activation. Genes Dev. 2005;19(12):1485–95. doi:10.1101/gad.341405.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Pippa R, Espinosa L, Gundem G, Garcia-Escudero R, Dominguez A, Orlando S, et al. p27Kip1 represses transcription by direct interaction with p130/E2F4 at the promoters of target genes. Oncogene. 2012;31(38):4207–20. doi:10.1038/onc.2011.582.

    Article  CAS  PubMed  Google Scholar 

  34. Greco V, Chen T, Rendl M, Schober M, Pasolli HA, Stokes N, et al. A two-step mechanism for stem cell activation during hair regeneration. Cell Stem Cell. 2009;4(2):155–69. doi:10.1016/j.stem.2008.12.009.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Ito M, Kizawa K, Hamada K, Cotsarelis G. Hair follicle stem cells in the lower bulge form the secondary germ, a biochemically distinct but functionally equivalent progenitor cell population, at the termination of catagen. Differentiation. 2004;72(9–10):548–57. doi:10.1111/j.1432-0436.2004.07209008.x.

    Article  PubMed  Google Scholar 

  36. Lee SE, Sada A, Zhang M, McDermitt DJ, Lu SY, Kemphues KJ, et al. High Runx1 levels promote a reversible, more-differentiated cell state in hair-follicle stem cells during quiescence. Cell Rep. 2014;6(3):499–513. doi:10.1016/j.celrep.2013.12.039.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Zhang YV, White BS, Shalloway DI, Tumbar T. Stem cell dynamics in mouse hair follicles: a story from cell division counting and single cell lineage tracing. Cell Cycle. 2010;9(8):1504–10.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Rompolas P, Mesa KR, Greco V. Spatial organization within a niche as a determinant of stem-cell fate. Nature. 2013;502(7472):513–8. doi:10.1038/nature12602.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Osorio KM, Lilja KC, Tumbar T. Runx1 modulates adult hair follicle stem cell emergence and maintenance from distinct embryonic skin compartments. J Cell Biol. 2011;193(1):235–50. doi:10.1083/jcb.201006068.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Hsu YC, Li L, Fuchs E. Transit-amplifying cells orchestrate stem cell activity and tissue regeneration. Cell. 2014;157(4):935–49. doi:10.1016/j.cell.2014.02.057.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Barry ER, Camargo FD. The Hippo superhighway: signaling crossroads converging on the Hippo/Yap pathway in stem cells and development. Curr Opin Cell Biol. 2013;25(2):247–53. doi:10.1016/j.ceb.2012.12.006.

    Article  CAS  PubMed  Google Scholar 

  42. Taylor G, Lehrer MS, Jensen PJ, Sun TT, Lavker RM. Involvement of follicular stem cells in forming not only the follicle but also the epidermis. Cell. 2000;102(4):451–61.

    Article  CAS  PubMed  Google Scholar 

  43. Ito M, Liu Y, Yang Z, Nguyen J, Liang F, Morris RJ, et al. Stem cells in the hair follicle bulge contribute to wound repair but not to homeostasis of the epidermis. Nat Med. 2005;11(12):1351–4. doi:10.1038/nm1328.

    Article  CAS  PubMed  Google Scholar 

  44. Horsley V, O’Carroll D, Tooze R, Ohinata Y, Saitou M, Obukhanych T, et al. Blimp1 defines a progenitor population that governs cellular input to the sebaceous gland. Cell. 2006;126(3):597–609. doi:10.1016/j.cell.2006.06.048.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Snippert HJ, Haegebarth A, Kasper M, Jaks V, van Es JH, Barker N, et al. Lgr6 marks stem cells in the hair follicle that generate all cell lineages of the skin. Science. 2010;327(5971):1385–9. doi:10.1126/science.1184733.

    Article  CAS  PubMed  Google Scholar 

  46. Jensen KB, Collins CA, Nascimento E, Tan DW, Frye M, Itami S, et al. Lrig1 expression defines a distinct multipotent stem cell population in mammalian epidermis. Cell Stem Cell. 2009;4(5):427–39. doi:10.1016/j.stem.2009.04.014.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Jaks V, Barker N, Kasper M, van Es JH, Snippert HJ, Clevers H, et al. Lgr5 marks cycling, yet long-lived, hair follicle stem cells. Nat Genet. 2008;40(11):1291–9. doi:10.1038/ng.239.

    Article  CAS  PubMed  Google Scholar 

  48. Nishimura EK, Jordan SA, Oshima H, Yoshida H, Osawa M, Moriyama M, et al. Dominant role of the niche in melanocyte stem-cell fate determination. Nature. 2002;416(6883):854–60. doi:10.1038/416854a.

    Article  CAS  PubMed  Google Scholar 

  49. Nishimura EK. Melanocyte stem cells: a melanocyte reservoir in hair follicles for hair and skin pigmentation. Pigment Cell Melanoma Res. 2011;24(3):401–10. doi:10.1111/j.1755-148X.2011.00855.x.

    Article  CAS  PubMed  Google Scholar 

  50. Tanimura S, Tadokoro Y, Inomata K, Binh NT, Nishie W, Yamazaki S, et al. Hair follicle stem cells provide a functional niche for melanocyte stem cells. Cell Stem Cell. 2011;8(2):177–87. doi:10.1016/j.stem.2010.11.029.

    Article  CAS  PubMed  Google Scholar 

  51. Chang CY, Pasolli HA, Giannopoulou EG, Guasch G, Gronostajski RM, Elemento O, et al. NFIB is a governor of epithelial-melanocyte stem cell behaviour in a shared niche. Nature. 2013;495(7439):98–102. doi:10.1038/nature11847.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Rabbani P, Takeo M, Chou W, Myung P, Bosenberg M, Chin L, et al. Coordinated activation of Wnt in epithelial and melanocyte stem cells initiates pigmented hair regeneration. Cell. 2011;145(6):941–55. doi:10.1016/j.cell.2011.05.004.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Rompolas P, Deschene ER, Zito G, Gonzalez DG, Saotome I, Haberman AM, et al. Live imaging of stem cell and progeny behaviour in physiological hair-follicle regeneration. Nature. 2012;487(7408):496–9. doi:10.1038/nature11218.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Chi W, Wu E, Morgan BA. Dermal papilla cell number specifies hair size, shape and cycling and its reduction causes follicular decline. Development. 2013;140(8):1676–83. doi:10.1242/dev.090662.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Rendl M, Lewis L, Fuchs E. Molecular dissection of mesenchymal-epithelial interactions in the hair follicle. PLoS Biol. 2005;3(11):e331. doi:10.1371/journal.pbio.0030331.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  56. Botchkarev VA, Botchkareva NV, Nakamura M, Huber O, Funa K, Lauster R, et al. Noggin is required for induction of the hair follicle growth phase in postnatal skin. FASEB J: official publication of the Federation of American Societies for Experimental Biology. 2001;15(12):2205–14. doi:10.1096/fj.01-0207com.

    Article  CAS  Google Scholar 

  57. Clavel C, Grisanti L, Zemla R, Rezza A, Barros R, Sennett R, et al. Sox2 in the dermal papilla niche controls hair growth by fine-tuning BMP signaling in differentiating hair shaft progenitors. Dev Cell. 2012;23(5):981–94. doi:10.1016/j.devcel.2012.10.013.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Woo WM, Zhen HH, Oro AE. Shh maintains dermal papilla identity and hair morphogenesis via a Noggin-Shh regulatory loop. Genes Dev. 2012;26(11):1235–46. doi:10.1101/gad.187401.112.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Hu B, Lefort K, Qiu W, Nguyen BC, Rajaram RD, Castillo E, et al. Control of hair follicle cell fate by underlying mesenchyme through a CSL-Wnt5a-FoxN1 regulatory axis. Genes Dev. 2010;24(14):1519–32. doi:10.1101/gad.1886910.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Rendl M, Polak L, Fuchs E. BMP signaling in dermal papilla cells is required for their hair follicle-inductive properties. Genes Dev. 2008;22(4):543–57. doi:10.1101/gad.1614408.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Enshell-Seijffers D, Lindon C, Kashiwagi M, Morgan BA. beta-catenin activity in the dermal papilla regulates morphogenesis and regeneration of hair. Dev Cell. 2010;18(4):633–42. doi:10.1016/j.devcel.2010.01.016.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Gat U, DasGupta R, Degenstein L, Fuchs E. De Novo hair follicle morphogenesis and hair tumors in mice expressing a truncated beta-catenin in skin. Cell. 1998;95(5):605–14.

    Article  CAS  PubMed  Google Scholar 

  63. Millar SE. Molecular mechanisms regulating hair follicle development. J Invest Dermatol. 2002;118(2):216–25. doi:10.1046/j.0022-202x.2001.01670.x.

    Article  CAS  PubMed  Google Scholar 

  64. Barrandon Y, Li V, Green H. New techniques for the grafting of cultured human epidermal cells onto athymic animals. J Invest Dermatol. 1988;91(4):315–8.

    Article  CAS  PubMed  Google Scholar 

  65. Driskell RR, Watt FM. Understanding fibroblast heterogeneity in the skin. Trends Cell Biol. 2015;25(2):92–9. doi:10.1016/j.tcb.2014.10.001.

    Article  CAS  PubMed  Google Scholar 

  66. Collins CA, Kretzschmar K, Watt FM. Reprogramming adult dermis to a neonatal state through epidermal activation of beta-catenin. Development. 2011;138(23):5189–99. doi:10.1242/dev.064592.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Biernaskie J, Paris M, Morozova O, Fagan BM, Marra M, Pevny L, et al. SKPs derive from hair follicle precursors and exhibit properties of adult dermal stem cells. Cell Stem Cell. 2009;5(6):610–23. doi:10.1016/j.stem.2009.10.019.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Rahmani W, Abbasi S, Hagner A, Raharjo E, Kumar R, Hotta A, et al. Hair follicle dermal stem cells regenerate the dermal sheath, repopulate the dermal papilla, and modulate hair type. Dev Cell. 2014;31(5):543–58. doi:10.1016/j.devcel.2014.10.022.

    Article  CAS  PubMed  Google Scholar 

  69. Festa E, Fretz J, Berry R, Schmidt B, Rodeheffer M, Horowitz M, et al. Adipocyte lineage cells contribute to the skin stem cell niche to drive hair cycling. Cell. 2011;146(5):761–71. doi:10.1016/j.cell.2011.07.019.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Mecklenburg L, Tobin DJ, Muller-Rover S, Handjiski B, Wendt G, Peters EM, et al. Active hair growth (anagen) is associated with angiogenesis. J Invest Dermatol. 2000;114(5):909–16. doi:10.1046/j.1523-1747.2000.00954.x.

    Article  CAS  PubMed  Google Scholar 

  71. Yano K, Brown LF, Detmar M. Control of hair growth and follicle size by VEGF-mediated angiogenesis. J Clin Investig. 2001;107(4):409–17. doi:10.1172/JCI11317.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Stenn KS, Fernandez LA, Tirrell SJ. The angiogenic properties of the rat vibrissa hair follicle associate with the bulb. J Invest Dermatol. 1988;90(3):409–11.

    Article  CAS  PubMed  Google Scholar 

  73. Amoh Y, Li L, Yang M, Moossa AR, Katsuoka K, Penman S, et al. Nascent blood vessels in the skin arise from nestin-expressing hair-follicle cells. Proc Natl Acad Sci USA. 2004;101(36):13291–5. doi:10.1073/pnas.0405250101.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Xiao Y, Woo WM, Nagao K, Li W, Terunuma A, Mukouyama YS, et al. Perivascular hair follicle stem cells associate with a venule annulus. J Invest Dermatol. 2013;133(10):2324–31. doi:10.1038/jid.2013.167.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Bigarella CL, Liang R, Ghaffari S. Stem cells and the impact of ROS signaling. Development. 2014;141(22):4206–18. doi:10.1242/dev.107086.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Hamanaka RB, Glasauer A, Hoover P, Yang S, Blatt H, Mullen AR et al. Mitochondrial reactive oxygen species promote epidermal differentiation and hair follicle development. Sci Signal. 2013;6(261):ra8. doi:10.1126/scisignal.2003638.

  77. Mohyeldin A, Garzon-Muvdi T, Quinones-Hinojosa A. Oxygen in stem cell biology: a critical component of the stem cell niche. Cell Stem Cell. 2010;7(2):150–61. doi:10.1016/j.stem.2010.07.007.

    Article  CAS  PubMed  Google Scholar 

  78. Rathman-Josserand M, Genty G, Lecardonnel J, Chabane S, Cousson A, Francois Michelet J, et al. Human hair follicle stem/progenitor cells express hypoxia markers. J Invest Dermatol. 2013;133(8):2094–7. doi:10.1038/jid.2013.113.

    Article  CAS  PubMed  Google Scholar 

  79. Chen X, Tian Y, Yao L, Zhang J, Liu Y. Hypoxia stimulates proliferation of rat neural stem cells with influence on the expression of cyclin D1 and c-Jun N-terminal protein kinase signaling pathway in vitro. Neuroscience. 2010;165(3):705–14. doi:10.1016/j.neuroscience.2009.11.007.

    Article  CAS  PubMed  Google Scholar 

  80. Gustafsson MV, Zheng X, Pereira T, Gradin K, Jin S, Lundkvist J, et al. Hypoxia requires notch signaling to maintain the undifferentiated cell state. Dev Cell. 2005;9(5):617–28. doi:10.1016/j.devcel.2005.09.010.

    Article  CAS  PubMed  Google Scholar 

  81. Botchkarev VA, Eichmuller S, Johansson O, Paus R. Hair cycle-dependent plasticity of skin and hair follicle innervation in normal murine skin. J Comp Neurol. 1997;386(3):379–95.

    Article  CAS  PubMed  Google Scholar 

  82. Brownell I, Guevara E, Bai CB, Loomis CA, Joyner AL. Nerve-derived sonic hedgehog defines a niche for hair follicle stem cells capable of becoming epidermal stem cells. Cell Stem Cell. 2011;8(5):552–65. doi:10.1016/j.stem.2011.02.021.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Christoph T, Muller-Rover S, Audring H, Tobin DJ, Hermes B, Cotsarelis G, et al. The human hair follicle immune system: cellular composition and immune privilege. Br J Dermatol. 2000;142(5):862–73.

    Article  CAS  PubMed  Google Scholar 

  84. Meyer KC, Klatte JE, Dinh HV, Harries MJ, Reithmayer K, Meyer W, et al. Evidence that the bulge region is a site of relative immune privilege in human hair follicles. Br J Dermatol. 2008;159(5):1077–85. doi:10.1111/j.1365-2133.2008.08818.x.

    CAS  PubMed  Google Scholar 

  85. Paus R, Nickoloff BJ, Ito T. A ‘hairy’ privilege. Trends Immunol. 2005;26(1):32–40. doi:10.1016/j.it.2004.09.014.

    Article  CAS  PubMed  Google Scholar 

  86. Osaka N, Takahashi T, Murakami S, Matsuzawa A, Noguchi T, Fujiwara T, et al. ASK1-dependent recruitment and activation of macrophages induce hair growth in skin wounds. J Cell Biol. 2007;176(7):903–9. doi:10.1083/jcb.200611015.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Castellana D, Paus R, Perez-Moreno M. Macrophages contribute to the cyclic activation of adult hair follicle stem cells. PLoS Biol. 2014;12(12):e1002002. doi:10.1371/journal.pbio.1002002.

    Article  PubMed  PubMed Central  Google Scholar 

  88. Kloepper JE, Kawai K, Bertolini M, Kanekura T, Paus R. Loss of gammadelta T cells results in hair cycling defects. J Invest Dermatol. 2013;133(6):1666–9. doi:10.1038/jid.2013.17.

    Article  CAS  PubMed  Google Scholar 

  89. Fujiwara H, Ferreira M, Donati G, Marciano DK, Linton JM, Sato Y, et al. The basement membrane of hair follicle stem cells is a muscle cell niche. Cell. 2011;144(4):577–89. doi:10.1016/j.cell.2011.01.014.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. White AC, Khuu JK, Dang CY, Hu J, Tran KV, Liu A, et al. Stem cell quiescence acts as a tumour suppressor in squamous tumours. Nat Cell Biol. 2014;16(1):99–107. doi:10.1038/ncb2889.

    Article  CAS  PubMed  Google Scholar 

  91. Liu JC, Lerou PH, Lahav G. Stem cells: balancing resistance and sensitivity to DNA damage. Trends Cell Biol. 2014;24(5):268–74. doi:10.1016/j.tcb.2014.03.002.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  92. Sotiropoulou PA, Candi A, Mascre G, De Clercq S, Youssef KK, Lapouge G, et al. Bcl-2 and accelerated DNA repair mediates resistance of hair follicle bulge stem cells to DNA-damage-induced cell death. Nat Cell Biol. 2010;12(6):572–82. doi:10.1038/ncb2059.

    Article  CAS  PubMed  Google Scholar 

  93. Rhee H, Polak L, Fuchs E. Lhx2 maintains stem cell character in hair follicles. Science. 2006;312(5782):1946–9. doi:10.1126/science.1128004.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Kadaja M, Keyes BE, Lin M, Pasolli HA, Genander M, Polak L, et al. SOX9: a stem cell transcriptional regulator of secreted niche signaling factors. Genes Dev. 2014;28(4):328–41. doi:10.1101/gad.233247.113.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Folgueras AR, Guo X, Pasolli HA, Stokes N, Polak L, Zheng D, et al. Architectural niche organization by LHX2 is linked to hair follicle stem cell function. Cell Stem Cell. 2013;13(3):314–27. doi:10.1016/j.stem.2013.06.018.

    Article  CAS  PubMed  Google Scholar 

  96. Vidal VP, Chaboissier MC, Lutzkendorf S, Cotsarelis G, Mill P, Hui CC, et al. Sox9 is essential for outer root sheath differentiation and the formation of the hair stem cell compartment. Curr Biol: CB. 2005;15(15):1340–51. doi:10.1016/j.cub.2005.06.064.

    Article  CAS  PubMed  Google Scholar 

  97. Nowak JA, Polak L, Pasolli HA, Fuchs E. Hair follicle stem cells are specified and function in early skin morphogenesis. Cell Stem Cell. 2008;3(1):33–43. doi:10.1016/j.stem.2008.05.009.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Nishimura EK, Granter SR, Fisher DE. Mechanisms of hair graying: incomplete melanocyte stem cell maintenance in the niche. Science. 2005;307(5710):720–4. doi:10.1126/science.1099593.

    Article  CAS  PubMed  Google Scholar 

  99. Lopez-Otin C, Blasco MA, Partridge L, Serrano M, Kroemer G. The hallmarks of aging. Cell. 2013;153(6):1194–217. doi:10.1016/j.cell.2013.05.039.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Flores I, Cayuela ML, Blasco MA. Effects of telomerase and telomere length on epidermal stem cell behavior. Science. 2005;309(5738):1253–6. doi:10.1126/science.1115025.

    Article  CAS  PubMed  Google Scholar 

  101. Flores I, Blasco MA. The role of telomeres and telomerase in stem cell aging. FEBS Lett. 2010;584(17):3826–30. doi:10.1016/j.febslet.2010.07.042.

    Article  CAS  PubMed  Google Scholar 

  102. Flores I, Canela A, Vera E, Tejera A, Cotsarelis G, Blasco MA. The longest telomeres: a general signature of adult stem cell compartments. Genes Dev. 2008;22(5):654–67. doi:10.1101/gad.451008.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Keyes BE, Segal JP, Heller E, Lien WH, Chang CY, Guo X, et al. Nfatc1 orchestrates aging in hair follicle stem cells. Proc Natl Acad Sci USA. 2013;110(51):E4950–9. doi:10.1073/pnas.1320301110.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. White AC, Lowry WE. Refining the role for adult stem cells as cancer cells of origin. Trends Cell Biol. 2015;25(1):11–20. doi:10.1016/j.tcb.2014.08.008.

    Article  CAS  PubMed  Google Scholar 

  105. Youssef KK, Van Keymeulen A, Lapouge G, Beck B, Michaux C, Achouri Y, et al. Identification of the cell lineage at the origin of basal cell carcinoma. Nat Cell Biol. 2010;12(3):299–305. doi:10.1038/ncb2031.

    CAS  PubMed  Google Scholar 

  106. Wang GY, Wang J, Mancianti ML, Epstein EH Jr. Basal cell carcinomas arise from hair follicle stem cells in Ptch1(±) mice. Cancer Cell. 2011;19(1):114–24. doi:10.1016/j.ccr.2010.11.007.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Kasper M, Jaks V, Are A, Bergstrom A, Schwager A, Svard J, et al. Wounding enhances epidermal tumorigenesis by recruiting hair follicle keratinocytes. Proc Natl Acad Sci USA. 2011;108(10):4099–104. doi:10.1073/pnas.1014489108.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. White AC, Tran K, Khuu J, Dang C, Cui Y, Binder SW, et al. Defining the origins of Ras/p53-mediated squamous cell carcinoma. Proc Natl Acad Sci USA. 2011;108(18):7425–30. doi:10.1073/pnas.1012670108.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Scheitz CJ, Lee TS, McDermitt DJ, Tumbar T. Defining a tissue stem cell-driven Runx1/Stat3 signalling axis in epithelial cancer. EMBO J. 2012;31(21):4124–39. doi:10.1038/emboj.2012.270.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Li S, Park H, Trempus CS, Gordon D, Liu Y, Cotsarelis G, et al. A keratin 15 containing stem cell population from the hair follicle contributes to squamous papilloma development in the mouse. Mol Carcinog. 2013;52(10):751–9. doi:10.1002/mc.21896.

    CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Molecular Biology and Genetics, Cornell University, 260 Biotechnology Bldg, Ithaca, NY, 14853, USA

    Alex B. Wang & Prachi Jain

  2. Department of Molecular Biology and Genetics, Cornell University, 258 Biotechnology Bldg, Ithaca, NY, 14853, USA

    Tudorita Tumbar

Authors
  1. Alex B. Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Prachi Jain
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Tudorita Tumbar
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Tudorita Tumbar .

Editor information

Editors and Affiliations

  1. 409 Lochaber Avenue, Ottowa ON, Ontario, Canada

    Kursad Turksen

Rights and permissions

Reprints and permissions

Copyright information

© 2015 Springer International Publishing Switzerland

About this chapter

Cite this chapter

Wang, A.B., Jain, P., Tumbar, T. (2015). The Hair Follicle Stem Cell Niche: The Bulge and Its Environment. In: Turksen, K. (eds) Tissue-Specific Stem Cell Niche. Stem Cell Biology and Regenerative Medicine. Springer, Cham. https://doi.org/10.1007/978-3-319-21705-5_1

Download citation

Publish with us

Policies and ethics

Search

Navigation