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.

The stem-cell niche as an entity of action

Abstract

Listen to an interview with David Scadden on the stem cells podcast

Stem-cell populations are established in ‘niches’ — specific anatomic locations that regulate how they participate in tissue generation, maintenance and repair. The niche saves stem cells from depletion, while protecting the host from over-exuberant stem-cell proliferation. It constitutes a basic unit of tissue physiology, integrating signals that mediate the balanced response of stem cells to the needs of organisms. Yet the niche may also induce pathologies by imposing aberrant function on stem cells or other targets. The interplay between stem cells and their niche creates the dynamic system necessary for sustaining tissues, and for the ultimate design of stem-cell therapeutics.

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: Refining elements necessary for an adult stem-cell niche.
Figure 2: Elements identified in stem-cell niches from various organisms and tissues.
Figure 3: Inputs feeding back on stem-cell function in the niche.
Figure 4: Potential niche contribution to dysplastic cell growth.

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

    Article  ADS  CAS  PubMed  Google Scholar 

  3. 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).

    Article  ADS  CAS  PubMed  Google Scholar 

  4. Crittenden, S. L. et al. A conserved RNA-binding protein controls germline stem cells in Caenorhabditis elegans. Nature 417, 660–663 (2002).

    Article  ADS  CAS  PubMed  Google Scholar 

  5. Calvi, L. M. et al. Osteoblastic cells regulate the haematopoietic stem cell niche. Nature 425, 841–846 (2003).

    Article  ADS  CAS  PubMed  Google Scholar 

  6. Zhang, J. et al. Identification of the haematopoietic stem cell niche and control of the niche size. Nature 425, 836–841 (2003).

    Article  ADS  CAS  PubMed  Google Scholar 

  7. Palmer, T. D., Willhoite, A. R. & Gage, F. H. Vascular niche for adult hippocampal neurogenesis. J. Comp. Neurol. 425, 479–494 (2000).

    Article  CAS  PubMed  Google Scholar 

  8. Kiel, M. J., Yilmaz, O. H., Iwashita, T., Terhorst, C. & Morrison, S. J. SLAM family receptors distinguish hematopoietic stem and progenitor cells and reveal endothelial niches for stem cells. Cell 121, 1109–1121 (2005).

    Article  CAS  PubMed  Google Scholar 

  9. Ohlstein, B. & Spradling, A. The adult Drosophila posterior midgut is maintained by pluripotent stem cells. Nature 439, 470–474 (2006).

    Article  ADS  CAS  PubMed  Google Scholar 

  10. Micchelli, C. A. & Perrimon, N. Evidence that stem cells reside in the adult Drosophila midgut epithelium. Nature 439, 475–479 (2006).

    Article  ADS  CAS  PubMed  Google Scholar 

  11. 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 

  12. 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 

  13. Garcion, E., Halilagic, A., Faissner, A. & Ffrench-Constant, C. Generation of an environmental niche for neural stem cell development by the extracellular matrix molecule tenascin C. Development 131, 3423–3432 (2004).

    Article  CAS  PubMed  Google Scholar 

  14. Ohta, M., Sakai, T., Saga, Y., Aizawa, S. & Saito, M. Suppression of hematopoietic activity in tenascin-C-deficient mice. Blood 91, 4074–4083 (1998).

    CAS  PubMed  Google Scholar 

  15. Stier, S. et al. Osteopontin is a hematopoietic stem cell niche component that negatively regulates stem cell pool size. J. Exp. Med. 201, 1781–1791 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Nilsson, S. K. et al. Osteopontin, a key component of the hematopoietic stem cell niche and regulator of primitive hematopoietic progenitor cells. Blood 106, 1232–1239 (2005).

    Article  CAS  PubMed  Google Scholar 

  17. Ashkar, S. et al. Eta-1 (osteopontin): an early component of type-1 (cell-mediated) immunity. Science 287, 860–864 (2000).

    Article  ADS  CAS  PubMed  Google Scholar 

  18. Rangaswami, H., Bulbule, A. & Kundu, G. C. Osteopontin: role in cell signaling and cancer progression. Trends Cell Biol. 16, 79–87 (2006).

    Article  CAS  PubMed  Google Scholar 

  19. Vermeulen, M. et al. Role of adhesion molecules in the homing and mobilization of murine hematopoietic stem and progenitor cells. Blood 92, 894–900 (1998).

    CAS  PubMed  Google Scholar 

  20. van der Loo, J. C. et al. VLA-5 is expressed by mouse and human long-term repopulating hematopoietic cells and mediates adhesion to extracellular matrix protein fibronectin. J. Clin. Invest. 102, 1051–1061 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  ADS  CAS  PubMed  Google Scholar 

  22. Tulina, N. & Matunis, E. Control of stem cell self-renewal in Drosophila spermatogenesis by JAK–STAT signaling. Science 294, 2546–2549 (2001).

    Article  ADS  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  24. Song, X. et al. Bmp signals from niche cells directly repress transcription of a differentiation-promoting gene, bag of marbles, in germline stem cells in the Drosophila ovary. Development 131, 1353–1364 (2004).

    Article  CAS  PubMed  Google Scholar 

  25. Chen, D. & McKearin, D. Dpp signaling silences bam transcription directly to establish asymmetric divisions of germline stem cells. Curr. Biol. 13, 1786–1791 (2003).

    Article  CAS  PubMed  Google Scholar 

  26. 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 

  27. 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).

    Article  CAS  PubMed  Google Scholar 

  28. St-Jacques, B. et al. Sonic hedgehog signaling is essential for hair development. Curr. Biol. 8, 1058–1068 (1998).

    Article  CAS  PubMed  Google Scholar 

  29. Levy, V., Lindon, C., Harfe, B. D. & Morgan, B. A. Distinct stem cell populations regenerate the follicle and interfollicular epidermis. Dev. Cell 9, 855–861 (2005).

    Article  CAS  PubMed  Google Scholar 

  30. Oro, A. E. & Higgins, K. Hair cycle regulation of Hedgehog signal reception. Dev. Biol. 255, 238–248 (2003).

    Article  CAS  PubMed  Google Scholar 

  31. Paladini, R. D., Saleh, J., Qian, C., Xu, G. X. & Rubin, L. L. Modulation of hair growth with small molecule agonists of the hedgehog signaling pathway. J. Invest. Dermatol. 125, 638–646 (2005).

    Article  CAS  PubMed  Google Scholar 

  32. Madison, B. B. et al. Epithelial hedgehog signals pattern the intestinal crypt–villus axis. Development 132, 279–289 (2005).

    Article  CAS  PubMed  Google Scholar 

  33. Batlle, E. et al. β-Catenin and TCF mediate cell positioning in the intestinal epithelium by controlling the expression of EphB/ephrinB. Cell 111, 251–263 (2002).

    Article  CAS  PubMed  Google Scholar 

  34. Adams, G. B. et al. Stem cell engraftment at the endosteal niche is specified by the calcium-sensing receptor. Nature 439, 599–603 (2006).

    Article  ADS  CAS  PubMed  Google Scholar 

  35. Ito, K. et al. Regulation of oxidative stress by ATM is required for self-renewal of haematopoietic stem cells. Nature 431, 997–1002 (2004).

    Article  ADS  CAS  PubMed  Google Scholar 

  36. Zou, Y. R., Kottmann, A. H., Kuroda, M., Taniuchi, I. & Littman, D. R. Function of the chemokine receptor CXCR4 in haematopoiesis and in cerebellar development. Nature 393, 595–599 (1998).

    Article  ADS  CAS  PubMed  Google Scholar 

  37. Ma, Q. et al. Impaired B-lymphopoiesis, myelopoiesis, and derailed cerebellar neuron migration in CXCR4- and SDF-1-deficient mice. Proc. Natl Acad. Sci. USA 95, 9448–9453 (1998).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  38. Semerad, C. L. et al. G-CSF potently inhibits osteoblast activity and CXCL12 mRNA expression in the bone marrow. Blood 106, 3020–3027 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Katayama, Y. et al. Signals from the sympathetic nervous system regulate hematopoietic stem cell egress from bone marrow. Cell 124, 407–421 (2006).

    Article  CAS  PubMed  Google Scholar 

  40. Lee, O. K. et al. Isolation of multipotent mesenchymal stem cells from umbilical cord blood. Blood 103, 1669–1675 (2004).

    Article  CAS  PubMed  Google Scholar 

  41. Rieger, K. et al. Mesenchymal stem cells remain of host origin even a long time after allogeneic peripheral blood stem cell or bone marrow transplantation. Exp. Hematol. 33, 605–611 (2005).

    Article  CAS  PubMed  Google Scholar 

  42. Johnson, J. et al. Oocyte generation in adult mammalian ovaries by putative germ cells in bone marrow and peripheral blood. Cell 122, 303–315 (2005).

    Article  CAS  PubMed  Google Scholar 

  43. Cleaver, O. & Melton, D. A. Endothelial signaling during development. Nature Med. 9, 661–668 (2003).

    Article  CAS  PubMed  Google Scholar 

  44. Sipkins, D. A. et al. In vivo imaging of specialized bone marrow endothelial microdomains for tumour engraftment. Nature 435, 969–973 (2005).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  45. Avecilla, S. T. et al. Chemokine-mediated interaction of hematopoietic progenitors with the bone marrow vascular niche is required for thrombopoiesis. Nature Med. 10, 64–71 (2004).

    Article  CAS  PubMed  Google Scholar 

  46. Nikolova, G. et al. The vascular basement membrane: a niche for insulin gene expression and β cell proliferation. Dev. Cell 10, 397–405 (2006).

    Article  CAS  PubMed  Google Scholar 

  47. Shen, Q. et al. Endothelial cells stimulate self-renewal and expand neurogenesis of neural stem cells. Science 304, 1338–1340 (2004).

    Article  ADS  CAS  PubMed  Google Scholar 

  48. Shi, S. & Gronthos, S. Perivascular niche of postnatal mesenchymal stem cells in human bone marrow and dental pulp. J. Bone Miner. Res. 18, 696–704 (2003).

    Article  PubMed  Google Scholar 

  49. Kaplan, R. N. et al. VEGFR1-positive haematopoietic bone marrow progenitors initiate the pre-metastatic niche. Nature 438, 820–827 (2005).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  50. 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).

    Article  CAS  PubMed  Google Scholar 

  51. Kai, T. & Spradling, A. An empty Drosophila stem cell niche reactivates the proliferation of ectopic cells. Proc. Natl Acad. Sci. USA 100, 4633–4638 (2003).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  52. Kai, T. & Spradling, A. Differentiating germ cells can revert into functional stem cells in Drosophila melanogaster ovaries. Nature 428, 564–569 (2004).

    Article  ADS  CAS  PubMed  Google Scholar 

  53. Lapidot, T. et al. A cell initiating human acute myeloid leukaemia after transplantation into SCID mice. Nature 367, 645–648 (1994).

    Article  ADS  CAS  PubMed  Google Scholar 

  54. Li, L. & Xie, T. Stem cell niche: structure and function. Annu. Rev. Cell Dev. Biol. 21, 605–631 (2005).

    Article  CAS  PubMed  Google Scholar 

  55. Ohlstein, B., Kai, T., Decotto, E. & Spradling, A. The stem cell niche: theme and variations. Curr. Opin. Cell Biol. 16, 693–699 (2004).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The author gratefully acknowledges H. Fleming and C. Lo Celso for their helpful input, C. Shambaugh for administrative assistance, and grants from the National Institutes of Health, the Burroughs Wellcome Trust, and the Leukemia and Lymphoma Society for supporting this work.

Author information

Authors and Affiliations

Authors

Ethics declarations

Competing interests

David Scadden is a founding member of Zhealix.

Additional information

Author Information Reprints and permissions information is available at npg.nature.com/reprintsandpermissions.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Scadden, D. The stem-cell niche as an entity of action. Nature 441, 1075–1079 (2006). https://doi.org/10.1038/nature04957

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature04957

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