Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Stem cells find their niche

Abstract

The concept that stem cells are controlled by particular microenvironments known as 'niches' has been widely invoked. But niches have remained largely a theoretical construct because of the difficulty of identifying and manipulating individual stem cells and their surroundings. Technical advances now make it possible to characterize small zones that maintain and control stem cell activity in several organs, including gonads, skin and gut. These studies are beginning to unify our understanding of stem cell regulation at the cellular and molecular levels, and promise to advance efforts to use stem cells therapeutically.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Niche structure.
Figure 2: Manipulating niches.
Figure 3: Male germ cell niches.
Figure 4: Female and hermaphrodite gonads.
Figure 5: Epithelial stem cell niches.

Similar content being viewed by others

References

  1. Schofield, R. The relationship between the spleen colony-forming cell and the haemopoietic stem cell. Blood Cells 4, 7–25 (1978).

    CAS  PubMed  Google Scholar 

  2. de Rooij, D. G. & Grootegoed, J. A. Spermatogonial stem cells. Curr. Opin. Cell. Biol. 10, 694–701 (1998).

    CAS  PubMed  Google Scholar 

  3. Kiger, A. A. & Fuller, M. T. in Stem Cell Biology (eds Marshak, D. R., Gardner, R. L. & Gottlieb, D.) 149–187 (Cold Spring Harbor Press, Cold Spring Harbor, 2001).

    Google Scholar 

  4. Brinster, R. L. & Zimmermann, J. W. Spermatogenesis following male germ-cell transplantation. Proc. Natl Acad. Sci. USA 91, 11298–11302 (1994).

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  5. Parreira, G. G. et al. Development of germ cell transplants in mice. Biol. Reprod. 59, 1360–1370 (1998).

    CAS  PubMed  Google Scholar 

  6. Dobrinski, I., Ogawa, T., Avarbock, M. R. & Brinster, R. L. Computer assisted image analysis to assess colonization of recipient seminiferous tubules by spermatogonial stem cells from transgenic donor mice. Mol. Reprod. Dev. 53, 142–148 (1999).

    CAS  PubMed  Google Scholar 

  7. Nagano, M., Avarbock, M. R. & Brinster, R. L. Pattern and kinetics of mouse donor spermatogonial stem cell colonization in recipient testes. Biol. Reprod. 60, 1429–1436 (1999).

    CAS  PubMed  Google Scholar 

  8. Till, J. E. & McCulloch, E. A. A direct measurement of the radiation sensitivity of normal mouse bone marrow cells. Radiat. Res. 14, 1419–1430 (1961).

    Google Scholar 

  9. Shinohara, T., Orwig, K. E., Avarbock, M. R. & Brinster, R. L. Remodeling of the postnatal mouse testis is accompanied by dramatic changes in stem cell number and niche accessibility. Proc. Natl Acad. Sci. USA 98, 6186–6191 (2001).

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  10. Ohta, H., Yomogida, K., Dohmae, K. & Nishimune, Y. Regulation of proliferation and differentiation in spermatogonial stem cells. The role of c-kit and its ligand SCF. Development 127, 2025–2131 (2000).

    Google Scholar 

  11. Shinohara T., Avarbock, M. R. & Brinster, R. L. β1- and α6-integrin are surface markers on mouse spermatogonial stem cells. Proc. Natl Acad. Sci. USA 96, 5504–5509 (1999).

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  12. Lawson, K. A. et al. Bmp4 is required for the generation of primordial germ cells in the mouse embryo. Genes Dev. 13, 424–436 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Ying Y., Liu, X. M., Marble, A., Lawson, K. A. & Zhao, G. Q. Requirement of Bmp8b for the generation of primordial germ cells in the mouse. Mol. Endocrinol. 14, 1053–1063 (2000).

    CAS  PubMed  Google Scholar 

  14. Wang R. A. & Zhao, G. Q. Transforming growth factor beta signal transducer Smad2 is expressed in mouse meiotic germ cells, Sertoli cells, and Leydig cells during spermatogenesis. Biol. Reprod. 61, 999–1004 (1999).

    CAS  PubMed  Google Scholar 

  15. Meng, X. et al. Regulation of cell fate decision of undifferentiated spermatogonia by GDNF. Science 287, 1489–1493 (2000).

    ADS  CAS  PubMed  Google Scholar 

  16. Tanaka, S. S. et al. The mouse homolog of Drosophila vasa is required for the development of male germ cells. Genes Dev. 14, 841–853 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Margolis J. & Spradling, A. Identification and behavior of epithelial stem cells in the Drosophila ovary. Development 121, 3797–3807 (1995).

    CAS  PubMed  Google Scholar 

  18. Gonczy, P. & DiNardo, S. The germ line regulates somatic cyst cell proliferation and fate during Drosophila spermatogenesis. Development 122, 2437–2447 (1996).

    CAS  PubMed  Google Scholar 

  19. Xie, T. & Spradling, A. C. Decapentaplegic is essential for the maintenance and division of the germline stem cells in the Drosophila ovary. Cell 94, 251–260 (1998).

    CAS  PubMed  Google Scholar 

  20. Kiger, A. A., White-Cooper, H. & Fuller, M. T. Somatic support cells restrict germline stem cell self-renewal and promote differentiation. Nature 407, 750–754 (2000).

    ADS  CAS  PubMed  Google Scholar 

  21. Tran, J., Brenner, T. J. & DiNardo, S. Somatic control over the germline stem cell lineage during Drosophila spermatogenesis. Nature 407, 754–757 (2000).

    ADS  CAS  PubMed  Google Scholar 

  22. Hardy, R. W., Tokuyasu, K. T., Lindsley, D. L. & Garavito, M. The germinal proliferation center in the testis of Drosophila melanogaster. J. Ultrastruct. Res. 69, 180–190 (1979).

    CAS  PubMed  Google Scholar 

  23. Sahut-Barnola, I., Godt, D., Laski, F. A. & Couderc, J. L. Drosophila ovary morphogenesis: analysis of terminal filament formation and identification of a gene required for this process. Dev. Biol. 170, 127–135 (1995).

    CAS  PubMed  Google Scholar 

  24. Lin, H. & Spradling, A. C. Germline stem cell division and egg chamber development in transplanted Drosophila germaria. Dev. Biol. 159, 140–152 (1993).

    CAS  PubMed  Google Scholar 

  25. King, F. J., Szakmary, A., Cox, D. N. & Lin, H. Yb modulates the divisions of both germline and somatic stem cells through piwi- and hh-mediated mechanisms in the Drosophila ovary. Mol. Cell 7, 497–508 (2001).

    CAS  PubMed  Google Scholar 

  26. de Cuevas, M. & Spradling, A. C. Morphogenesis of the Drosophila fusome and its implications for oocyte specification. Development 125, 2781–2789 (1998).

    CAS  PubMed  Google Scholar 

  27. Deng, W. & Lin, H. Spectrosomes and fusomes anchor mitotic spindles during asymmetric germ cell divisions and facilitate the formation of a polarized microtubule array for oocyte specification in Drosophila. Dev. Biol. 189, 79–94 (1997).

    CAS  PubMed  Google Scholar 

  28. Lin, H. & Spradling, A. C. A novel group of pumilio mutations affects the asymmetric division of germline stem cells in the Drosophila ovary. Development 124, 2463–2476 (1997).

    CAS  PubMed  Google Scholar 

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

    ADS  CAS  PubMed  Google Scholar 

  30. Twombly, V. et al. The TGF-β signalling pathway is essential for Drosophila oogenesis. Development 122, 1555–1565 (1996).

    CAS  PubMed  Google Scholar 

  31. Cox, D. N., Chao, A. & Lin, H. piwi encodes a nucleoplasmic factor whose activity modulates the number and division rate of germline stem cells. Development 127, 503–514 (2000).

    CAS  PubMed  Google Scholar 

  32. Cox, D. N. et al. A novel class of evolutionarily conserved genes defined by piwi are essential for stem cell self-renewal. Genes Dev. 12, 3715–3727 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Moussian, B., Schoof, H., Haecker, A., Jurgens, G. & Laux, T. Role of the ZWILLE gene in the regulation of central shoot meristem cell fate during Arabidopsis embryogenesis. EMBO J. 17, 1799–1809 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Sharma, A. K. et al. Human CD34+ stem cells express the hiwi gene, a human homologue of the Drosophila gene piwi. Blood 97, 426–434 (2001).

    CAS  PubMed  Google Scholar 

  35. Forbes, A. & Lehmann, R. Nanos and Pumilio have critical roles in the development and function of Drosophila germline stem cells. Development 125, 679–690 (1998).

    CAS  PubMed  Google Scholar 

  36. Ohlstein, B., Lavoie, C. A., Vef, O., Gateff, E. & McKearin, D. M. The Drosophila cystoblast differentiation factor, benign gonial cell neoplasm, is related to DExH-box proteins and interacts genetically with bag-of-marbles. Genetics 155, 1809–1819 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Gonczy, P., Matunis, E. & DiNardo, S. bag-of-marbles and benign gonial cell neoplasm act in the germline to restrict proliferation during Drosophila spermatogenesis. Development 124, 4361–4371 (1997).

    CAS  PubMed  Google Scholar 

  38. Henderson, S. T., Gao, D., Lambie, E. J. & Kimble, J. lag-2 may encode a signaling ligand for the GLP-1 and LIN-12 receptors of C. elegans. Development 120, 2913–2924 (1994).

    CAS  PubMed  Google Scholar 

  39. Austin, J. & Kimble, J. glp-1 is required in the germ line for regulation of the decision between mitosis and meiosis in C. elegans. Cell 51, 589–599 (1987).

    CAS  PubMed  Google Scholar 

  40. Berry, L. W., Westlund, B. & Schedl, T. Germ-line tumor formation caused by activation of glp-1, a Caenorhabditis elegans member of the Notch family of receptors. Development 124, 925–936 (1997).

    CAS  PubMed  Google Scholar 

  41. Kadyk, L. C., Kimble, J. Genetic regulation of entry into meiosis in Caenorhabditis elegans. Development 125, 1803–1813 (1998).

    CAS  PubMed  Google Scholar 

  42. Jonason, A. S. et al. Frequent clones of p53-mutated keratinocytes in normal human skin. Proc. Natl Acad. Sci. USA 95, 14025–14029 (1996).

    ADS  Google Scholar 

  43. Watt, F. in Stem Cell Biology (eds Marshak, D. R., Gardner, R. L. & Gottlieb, D.) 439–453 (Cold Spring Harbor Press, Cold Spring Harbor, 2001).

    Google Scholar 

  44. Lavker, R. M. & Sun, T.-T. Heterogeneity in epidermal basal cell keratinocytes: morphological and functional correlations. Science 215, 1239–1241 (1982).

    ADS  CAS  PubMed  Google Scholar 

  45. Cotsarelis, G., Cheng, S. Z., Dong, G., Sun, T.-T. & Lavker, R. M. Existence of slow-cycling limbal epithelial basal cells that can be preferentially stimulated to proliferate: implications on epithelial stem cells. Cell 57, 201–209 (1989).

    CAS  PubMed  Google Scholar 

  46. Rochat, A., Kobayashi, K. & Barrandon, Y. Location of stem cells of human hair follicles by clonal analysis. Cell 76, 1063–1073 (1994).

    CAS  PubMed  Google Scholar 

  47. Taylor, G., Lehrer, M. S., Jensen, P. J., Sun, T.-T. & Lavker, R. M. Involvement of follicular stem cells in forming not only the follicle but also the epidermis. Cell 102, 451–461 (2000).

    CAS  PubMed  Google Scholar 

  48. Oshima, H., Rochat, A., Kedzia, C., Kobayashi, K. & Barrandon, Y. Morphogenesis and renewal of hair follicles from adult multipotent stem cells. Cell 104, 233–245 (2001).

    CAS  PubMed  Google Scholar 

  49. Stenn, K. S. & Paus, R. Controls of hair follicle cycling. Physiol. Rev. 81, 449–494 (2001).

    CAS  PubMed  Google Scholar 

  50. Finch, P. W., Rubin, J. S., Miki, T., Ron, D. & Aaronson, S. A. Human KGF is FGF-related with properties of a paracrine effector of epithelial cell growth. Science 245, 752–755 (1989).

    ADS  CAS  PubMed  Google Scholar 

  51. Brakebusch, C. et al. Skin and hair follicle integrity is crucially dependent on β1 integrin expression on keratinocytes. EMBO J. 19, 3990–4003 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Raghavan, S., Bauer, C., Mundschau, G., Li, Q. & Fuchs, E. Conditional ablation of beta1 integrin in skin. Severe defects in epidermal proliferation, basement membrane formation, and hair follicle invagination. J. Cell Biol. 150, 1149–1160 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Vasioukhin, V., Bauer, C., Degenstein, L., Wise, B. & Fuchs, E. Hyperproliferation and defects in epithelial polarity upon conditional ablation of α-catenin in skin. Cell 104, 605–617 (2001).

    CAS  PubMed  Google Scholar 

  54. Kulessa, H., Turk, G. & Hogan, B. L. Inhibition of Bmp signalling affects growth and differentiation in the anagen hair follicle. EMBO J. 19, 6664–6674 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Chiang, C. et al. Essential role for Sonic hedgehog during hair follicle morphogenesis. Dev. Biol. 205, 1–9 (1999).

    CAS  PubMed  Google Scholar 

  56. Gambardella, L., Schneider-Maunoury, S., Voiculescu, O., Charnay, P. & Barrandon, Y. Pattern of expression of the transcription factor Krox-20 in mouse hair follicle. Mech. Dev. 96, 215–218 (2000).

    CAS  PubMed  Google Scholar 

  57. van Genderen, C. et al. Development of several organs that require inductive epithelial-mesenchymal interactions is impaired in Lef-1-deficient mice. Genes Dev. 8, 2691–2703 (1994).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  59. Huelsken, J., Vogel, R., Erdmann, B. & Cotsarelis, G. β-Catenin controls hair follicle morphogenesis and stem cell differentiation in the skin. Cell 105, 533–545 (2001).

    CAS  PubMed  Google Scholar 

  60. Gat, U., DasGupta, R., Degenstein, L. & Fuchs, E. De novo hair follicle morphogenesis and hair tumors in mice expressing a truncated β-catenin in skin. Cell 95, 605–614 (1998).

    CAS  PubMed  Google Scholar 

  61. Chan, E. F., Gat, U., McNiff, J. M. & Fuchs, E. A common human skin tumour is caused by activating mutations in β-catenin. Nature Genet. 21, 410–413 (1999).

    CAS  PubMed  Google Scholar 

  62. Kishimoto, J., Burgeson, R. E. & Morgan, B. A. Wnt signalling maintains the hair-inducing activity of the dermal papilla. Genes Dev. 14, 1181–1185 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Drummond-Barbosa, D. & Spradling, A. C. Stem cells and their progeny respond to nutritional changes during Drosophila oogenesis. Dev. Biol. 231, 265–278 (2001).

    CAS  PubMed  Google Scholar 

  64. Zhang, Y. & Kalderon, D. Hedgehog acts as a somatic stem cell factor in the Drosophila ovary. Nature 410, 599–604 (2001).

    ADS  CAS  PubMed  Google Scholar 

  65. Forbes, A. J., Lin, H., Ingham, P. W. & Spradling, A. C. hedgehog is required for the proliferation and specification of ovarian somatic cells prior to egg chamber formation in Drosophila. Development 122, 1125–1135 (1996).

    CAS  PubMed  Google Scholar 

  66. Forbes, A. J., Spradling, A. C., Ingham, P. W. & Lin, H. The role of segment polarity genes during early oogenesis in Drosophila. Development 122, 3283–3294 (1996).

    CAS  PubMed  Google Scholar 

  67. Zhang, Y. & Kalderon, D. Regulation of cell proliferation and patterning in Drosophila oogenesis by Hedgehog signaling. Development 127, 2165–2176 (2000).

    CAS  PubMed  Google Scholar 

  68. Bjerknes, M. & Cheng, H. Clonal analysis of mouse intestinal epithelial progenitors. Gastroenterology 116, 7–14 (1999).

    CAS  PubMed  Google Scholar 

  69. Wong, M. H., Saam, J. R., Stappenbeck, T. S., Rexer, C. H. & Gordon, J. I. Genetic mosaic analysis based on Cre recombinase and navigated laser capture microdissection. Proc. Natl Acad. Sci. USA 97, 12601–12606 (2000).

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  70. Novelli, M. R. et al. Polyclonal origin of colonic adenomas in an XO/XY patient with FAP. Science 272, 1187–1190 (1996).

    ADS  CAS  PubMed  Google Scholar 

  71. Garabedian, E. M., Lisa, J. J., Roberts, M., McNevin, S. & Gordon, J. I. Examining the role of Paneth cells in the small intestine by lineage ablation in transgenic mice. J. Biol. Chem. 272, 23729–23740 (1997).

    CAS  PubMed  Google Scholar 

  72. Rindi, G. et al. Targeted ablation of secretin-producing cells in transgenic mice reveals a common differentiation pathway with multiple enteroendocrine cell lineages in the small intestine. Development 126, 4149–4156 (1999).

    CAS  PubMed  Google Scholar 

  73. Korinek, V. et al. Depletion of epithelial stem-cell compartments in the small intestine of mice lacking Tcf-4. Nature Genet. 19, 379–383 (1998).

    CAS  PubMed  Google Scholar 

  74. Kaestner, K. H., Silberg, D. G., Traber, P. G. & Schutz, G. The mesenchymal winged helix transcription factor Fkh6 is required for the control of gastrointestinal proliferation and differentiation. Genes Dev. 11, 1583–1595 (1997).

    CAS  PubMed  Google Scholar 

  75. Hardy, M. H. The secret life of the hair follicle. Trends Genet. 8, 159–166 (1992).

    Google Scholar 

  76. Bjerknes, M., Cheng, H., Hay, K. & Gallinger, S. APC mutation and the crypt cycle in murine and human intestine. Am. J. Pathol. 150, 833–839 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  77. Wright, N. A. Epithelial stem cell repertoire in the gut: clues to the origin of cell lineages, proliferative units and cancer. Int. J. Exp. Pathol. 81, 117–143 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  78. van Beek, M. E. A. B., Meistrich, M. L. & de Rooij, D. G. Probability of self-renewing divisions of spermatogonial stem cells in colonies, formed after fission neutron irradiation. Cell. Tissue Kinet. 23, 1–16 (1990).

    CAS  PubMed  Google Scholar 

  79. Hebert, J. M., Rosenquist, T., Gotz, J. & Martin, G. R. FGF5 as a regulator of the hair growth cycle: evidence from targeted and spontaneous mutations. Cell 78, 1017–1025 (1994).

    CAS  PubMed  Google Scholar 

  80. Murillas, R. et al. Expression of a dominant negative mutant of epidermal growth factor receptor in the epidermis of transgenic mice elicits striking alterations in hair follicle development and skin structure. EMBO J. 14, 5216–5223 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  81. Sibilia, M. & Wagner, E. F. Strain-dependent epithelial defects in mice lacking the EGF receptor. Science 269, 234–238 (1995).

    ADS  CAS  PubMed  Google Scholar 

  82. Luetteke, N. C. et al. TGF- α deficiency results in hair follicle and eye abnormalities in targeted and waved-1 mice. Cell 73, 263–278 (1993).

    CAS  PubMed  Google Scholar 

  83. Panteleyev, A. A. et al. Towards defining the pathogenesis of the hairless phenotype. J. Invest. Dermatol. 110, 902–907 (1998).

    CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Spradling, A., Drummond-Barbosa, D. & Kai, T. Stem cells find their niche. Nature 414, 98–104 (2001). https://doi.org/10.1038/35102160

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/35102160

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing