1. Center for Regenerative Medicine and
2. Blood Transfusion Service, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA
3. Harvard Stem Cell Institute, Harvard University, Cambridge, Massachusetts 02138, USA
4. Renal Division and
5. Endocrine-Hypertension Division, Membrane Biology Program, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA
6. †Present address: Department of Pathology, Dartmouth-Hitchcock Medical Center, Dartmouth Medical School, Lebanon, New Hampshire 03756, USA

Correspondence to: David T. Scadden^1,3 Correspondence and requests for materials should be addressed to D.T.S. (Email: scadden.david@mgh.harvard.edu).

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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