Stem cell engraftment at the endosteal niche is specified by the calcium-sensing receptor (original) (raw)

Nature volume 439, pages 599–603 (2006)Cite this article

Abstract

During mammalian ontogeny, haematopoietic stem cells (HSCs) translocate from the fetal liver to the bone marrow, where haematopoiesis occurs throughout adulthood1. Unique features of bone that contribute to a microenvironmental niche for stem cells might include the known high concentration of calcium ions at the HSC-enriched endosteal surface. Cells respond to extracellular ionic calcium concentrations through the seven-transmembrane-spanning calcium-sensing receptor (CaR), which we identified as being expressed on HSCs. Here we show that, through the CaR, the simple ionic mineral content of the niche may dictate the preferential localization of adult mammalian haematopoiesis in bone. Antenatal mice deficient in CaR had primitive haematopoietic cells in the circulation and spleen, whereas few were found in bone marrow. CaR-/- HSCs from fetal liver were normal in number, in proliferative and differentiative function, and in migration and homing to the bone marrow. Yet they were highly defective in localizing anatomically to the endosteal niche, behaviour that correlated with defective adhesion to the extracellular matrix protein, collagen I. CaR has a function in retaining HSCs in close physical proximity to the endosteal surface and the regulatory niche components associated with it.

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Acknowledgements

We thank C. Seidman and J. Seidman for access to CaR-/- mice. Financial support for this work was provided by the American Society of Hematology (G.B.A.), the Burroughs Wellcome Fund, the Doris Duke Charitable Trust (D.T.S.) and the National Institutes of Health (M.R.P., E.B. and D.T.S.).

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Author notes

  1. Zbigniew M. Szczepiorkowski
    Present address: Department of Pathology, Dartmouth-Hitchcock Medical Center, Dartmouth Medical School, Lebanon, New Hampshire, 03756, USA

Authors and Affiliations

  1. Center for Regenerative Medicine,
    Gregor B. Adams, Karissa T. Chabner, Ian R. Alley, Douglas P. Olson, Zbigniew M. Szczepiorkowski, Mark C. Poznansky & David T. Scadden
  2. Blood Transfusion Service, Massachusetts General Hospital, Harvard Medical School, Massachusetts, 02114, Boston, USA
    Zbigniew M. Szczepiorkowski
  3. Harvard Stem Cell Institute, Harvard University, Massachusetts, 02138, Cambridge, USA
    Gregor B. Adams, Karissa T. Chabner, Ian R. Alley & David T. Scadden
  4. Renal Division, Massachusetts, 02115, Boston, USA
    Claudine H. Kos & Martin R. Pollak
  5. Endocrine-Hypertension Division, Membrane Biology Program, Brigham and Women's Hospital, Harvard Medical School, Massachusetts, 02115, Boston, USA
    Edward M. Brown

Authors

  1. Gregor B. Adams
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  2. Karissa T. Chabner
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  3. Ian R. Alley
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  4. Douglas P. Olson
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  5. Zbigniew M. Szczepiorkowski
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  6. Mark C. Poznansky
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  7. Claudine H. Kos
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  8. Martin R. Pollak
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  9. Edward M. Brown
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  10. David T. Scadden
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Corresponding author

Correspondence toDavid T. Scadden.

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Supplementary information

Supplementary Figure 1

Quantitative PCR analysis of car expression. RNA was obtained from purified CD11b+, CD3+ and lin-c-Kit+Sca-1+ (KLS) or lin-c-Kit+ (KL) cells and cDNA was made. Expression of car was then determined by real time PCR. Expression levels of car are shown relative to the expression of hprt. (PDF 11 kb)

Supplementary Figure 2

Cell cycle analysis of primitive bone marrow cells from mice transplanted with CaR+/+ or Ca R-/- cells. Mononuclear cells from E17.5 fetal liver were transplanted into lethally irradiated wild-type hosts. Eight weeks following injection of the cells, the bone marrow was analyzed for cell cycle status. (PDF 16 kb)

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Adams, G., Chabner, K., Alley, I. et al. Stem cell engraftment at the endosteal niche is specified by the calcium-sensing receptor.Nature 439, 599–603 (2006). https://doi.org/10.1038/nature04247

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Editorial Summary

Stem-cell guidance

Haematopoietic stem cells ‘home’ to the bone marrow during embryogenesis and after bone marrow transplants. With the exception of integrins, the molecules that mediate this process are largely unknown. Now Adams et al. have identified another factor essential for homing, a membrane-spanning molecule called calcium-sensing receptor (CaR). Cells lacking CaR divide normally, but the newly formed cells are unable to migrate and home to the bone marrow. This newly recognized participant in the localization and engraftment of stem cells provides a potential target for affecting that process.