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The hematopoietic stem cell in its place

Abstract

A signature characteristic of stem cells is their ability to self-renew, affording a theoretically limitless ability to produce daughter cells and their descendents. This near-timeless dimension of stem cell function is not free of the constraints of place. The idea that highly specialized 'microenvironmental' cues participate in the regulation of stem cells has evidence in classic embryology and more recently in adult stem cells through the use of model organisms. There is now ample evidence that an anatomically defined, specifically constituted place represents the niche for hematopoietic and other tissue-specific stem cells. This review provides a conceptual framework and detailed account of the hematopoietic stem cell niche as defined at present. The components are assembling into a more complex view of the niche and may now be amenable to examination as a system and possibly to alteration to affect outcomes in immune regeneration.

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Figure 1: Interactions in the endosteal niche.

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References

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

    Article  CAS  Google Scholar 

  2. 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  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  4. 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 

  5. 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  Google Scholar 

  6. Abkowitz, J.L., Catlin, S.N., McCallie, M.T. & Guttorp, P. Evidence that the number of hematopoietic stem cells per animal is conserved in mammals. Blood 100, 2665–2667 (2002).

    Article  CAS  Google Scholar 

  7. Song, X., Zhu, C.H., Doan, C. & Xie, T. Germline stem cells anchored by adherens junctions in the Drosophila ovary niches. Science 296, 1855–1857 (2002).

    Article  CAS  Google Scholar 

  8. Yamashita, Y.M., Jones, D.L. & Fuller, M.T. Orientation of asymmetric stem cell division by the APC tumor suppressor and centrosome. Science 301, 1547–1550 (2003).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  10. Arai, F. et al. Tie2/angiopoietin-1 signaling regulates hematopoietic stem cell quiescence in the bone marrow niche. Cell 118, 149–161 (2004).

    Article  CAS  Google Scholar 

  11. Decotto, E. & Spradling, A.C. The Drosophila ovarian and testis stem cell niches: similar somatic stem cells and signals. Dev. Cell 9, 501–510 (2005).

    Article  CAS  Google Scholar 

  12. Crittenden, S.L. et al. Regulation of the mitosis/meiosis decision in the Caenorhabditis elegans germline. Phil. Trans. R. Soc. Lond. B 358, 1359–1362 (2003).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  14. 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  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  16. Palis, J., Robertson, S., Kennedy, M., Wall, C. & Keller, G. Development of erythroid and myeloid progenitors in the yolk sac and embryo proper of the mouse. Development 126, 5073–5084 (1999).

    CAS  PubMed  Google Scholar 

  17. Muller, A.M., Medvinsky, A., Strouboulis, J., Grosveld, F. & Dzierzak, E. Development of hematopoietic stem cell activity in the mouse embryo. Immunity 1, 291–301 (1994).

    Article  CAS  Google Scholar 

  18. Gekas, C., Dieterlen-Lievre, F., Orkin, S.H. & Mikkola, H.K. The placenta is a niche for hematopoietic stem cells. Dev. Cell 8, 365–375 (2005).

    Article  CAS  Google Scholar 

  19. Wright, D.E., Wagers, A.J., Gulati, A.P., Johnson, F.L. & Weissman, I.L. Physiological migration of hematopoietic stem and progenitor cells. Science 294, 1933–1936 (2001).

    Article  CAS  Google Scholar 

  20. Frimberger, A.E. et al. The fleet feet of haematopoietic stem cells: rapid motility, interaction and proteopodia. Br. J. Haematol. 112, 644–654 (2001).

    Article  CAS  Google Scholar 

  21. Udani, V.M. et al. Hematopoietic stem cells give rise to perivascular endothelial-like cells during brain tumor angiogenesis. Stem Cells Dev. 14, 478–486 (2005).

    Article  CAS  Google Scholar 

  22. Stewart, F.M., Crittenden, R.B., Lowry, P.A., Pearson-White, S. & Quesenberry, P.J. Long-term engraftment of normal and post-5-fluorouracil murine marrow into normal nonmyeloablated mice. Blood 81, 2566–2571 (1993).

    CAS  PubMed  Google Scholar 

  23. Nilsson, S.K., Johnston, H.M. & Coverdale, J.A. Spatial localization of transplanted hemopoietic stem cells: inferences for the localization of stem cell niches. Blood 97, 2293–2299 (2001).

    Article  CAS  Google Scholar 

  24. Taichman, R.S. & Emerson, S.G. Human osteoblasts support hematopoiesis through the production of granulocyte colony-stimulating factor. J. Exp. Med. 179, 1677–1682 (1994).

    Article  CAS  Google Scholar 

  25. Taichman, R., Reilly, M., Verma, R., Ehrenman, K. & Emerson, S. Hepatocyte growth factor is secreted by osteoblasts and cooperatively permits the survival of haematopoietic progenitors. Br. J. Haematol. 112, 438–448 (2001).

    Article  CAS  Google Scholar 

  26. Mancini, S.J. et al. Jagged1-dependent Notch signaling is dispensable for hematopoietic stem cell self-renewal and differentiation. Blood 105, 2340–2342 (2005).

    Article  CAS  Google Scholar 

  27. Visnjic, D. et al. Hematopoiesis is severely altered in mice with an induced osteoblast deficiency. Blood 103, 3258–3264 (2004).

    Article  CAS  Google Scholar 

  28. 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  Google Scholar 

  29. 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  Google Scholar 

  30. Wilson, A. et al. c-Myc controls the balance between hematopoietic stem cell self-renewal and differentiation. Genes Dev. 18, 2747–2763 (2004).

    Article  CAS  Google Scholar 

  31. Denhardt, D.T., Noda, M., O'Regan, A.W., Pavlin, D. & Berman, J.S. Osteopontin as a means to cope with environmental insults: regulation of inflammation, tissue remodeling, and cell survival. J. Clin. Invest. 107, 1055–1061 (2001).

    Article  CAS  Google Scholar 

  32. 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  Google Scholar 

  33. 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  Google Scholar 

  34. Silver, I.A., Murrills, R.J. & Etherington, D.J. Microelectrode studies on the acid microenvironment beneath adherent macrophages and osteoclasts. Exp. Cell Res. 175, 266–276 (1988).

    Article  CAS  Google Scholar 

  35. Chattopadhyay, N., Vassilev, P.M. & Brown, E.M. Calcium-sensing receptor: roles in and beyond systemic calcium homeostasis. Biol. Chem. 378, 759–768 (1997).

    CAS  PubMed  Google Scholar 

  36. Adams, G.B. et al. Stem cell engraftment at the endosteal niche is specified by the calcium-sensing receptor. Nature 439, 599–603 (2005).

    Article  Google Scholar 

  37. Deguchi, K. et al. Excessive extramedullary hematopoiesis in Cbfa1-deficient mice with a congenital lack of bone marrow. Biochem. Biophys. Res. Commun. 255, 352–359 (1999).

    Article  CAS  Google Scholar 

  38. Yoshida, H. et al. The murine mutation osteopetrosis is in the coding region of the macrophage colony stimulating factor gene. Nature 345, 442–444 (1990).

    Article  CAS  Google Scholar 

  39. 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  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank C. Shambaugh for administrative assistance. Supported in part by the National Institutes of Health (HL081030 and HL44851), the Burroughs Wellcome Fund and the Leukemia & Lymphoma Society.

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Correspondence to David T Scadden.

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Competing interests

D.T.S. is a founder of Zhealix, a company targeting stem cells pharmacologically.

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Adams, G., Scadden, D. The hematopoietic stem cell in its place. Nat Immunol 7, 333–337 (2006). https://doi.org/10.1038/ni1331

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