Stem cell engraftment at the endosteal niche is specified by the calcium-sensing receptor

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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Figure 1: CaR -/- mice have a hypocellular bone marrow.
Figure 2: CaR -/- mice have aberrant localization of primitive haematopoietic cells.
Figure 3: CaR -/- HSC defects are stem cell autonomous, specific to the bone marrow microenvironmental niche.
Figure 4: CaR -/- HSCs are unable to localize to the endosteal niche.

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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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Correspondence to David 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 CaR-/- 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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