HSCs find their niche

In adults, haematopoietic stem cells (HSCs) — the primitive progenitors from which all cells of the immune system are derived — are located in the bone marrow, close to the endosteal surfaces of bone. Many cell-surface receptors have been implicated in controlling the localization of HSCs to this endosteal niche. However, a report published in Nature now shows that expression of calcium-sensing receptor (CaR) by HSCs is crucial for their lodgement in the endosteal niche.

The endosteum is a site of constant bone modelling and remodelling, and as such it is characterized by high concentrations of calcium ions (Ca²⁺). CaR is one receptor by which cells sense the extracellular concentration of Ca²⁺, and because some haematopoietic cells have previously been shown to express CaR, Adams et al. set out to investigate whether CaR is important for HSC localization or function in the endosteal niche. CaR was shown to be expressed by lineage (Lin)⁻ stem-cell antigen 1 (SCA1)⁺KIT⁺ cells (known as LSK cells) isolated from the bone marrow, a population that is enriched in cells with the functional properties of stem cells.

expression of CaR by HSCs is required for their lodgement in the endosteal niche

Consistent with the hypothesis that expression of CaR by LSK cells is important for their localization or function in the endosteal niche, the bone marrow of CaR-deficient mice was shown to contain markedly fewer LSK cells than that of CaR-sufficient littermate control mice. Furthermore, the number of cells able to initiate long-term cultures (an in vitro functional assay for HSCs) was also markedly decreased in the bone marrow of CaR-deficient mice. By contrast, the number of LSK cells in the spleen and the blood of CaR-deficient mice was increased. Importantly, the aberrant localization of LSK cells in CaR-deficient mice was not a result of intrinsic HSC abnormalities, because fetal-liver LSK cells from these mice were phenotypically and functionally normal. However, following transfer to lethally irradiated wild-type recipients, CaR-deficient fetal-liver cells failed to accumulate in the bone marrow, indicating a role for CaR in regulating HSC localization in the endosteal niche.

The defect in localization of CaR-deficient HSCs in the endosteal niche could be a result of aberrant homing to the bone marrow or an inability to lodge in the endosteal niche. CaR-deficient fetal-liver LSK cells were found to express normal amounts of cell-surface molecules involved in homing to the bone marrow, and they were found to enter the bone marrow as efficiently as wild-type fetal-liver cells. By contrast, CaR-deficient fetal-liver cells were markedly impaired in their ability to bind the extracellular-matrix component collagen type I and showed reduced ability to physically associate with the endosteal surface.

These data indicate that expression of CaR by HSCs is required for their lodgement in the endosteal niche. These results provide a mechanism for HSC engraftment in the bone marrow during ontogeny and, as the authors suggest, have important implications for stem-cell transplantation therapies.