CXCL12 in early mesenchymal progenitors is required for haematopoietic stem-cell maintenance

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Haematopoietic stem cells (HSCs) primarily reside in the bone marrow where signals generated by stromal cells regulate their self-renewal, proliferation and trafficking. Endosteal osteoblasts1,2and perivascular stromal cells including endothelial cells3, CXCL12-abundant reticular cells4,5, leptin-receptor-positive stromal cells6, and nestin–green fluorescent protein (GFP)-positive mesenchymal progenitors7have all been implicated in HSC maintenance. However, it is unclear whether specific haematopoietic progenitor cell (HPC) subsets reside in distinct niches defined by the surrounding stromal cells and the regulatory molecules they produce. CXCL12 (chemokine (C–X–C motif) ligand 12) regulates both HSCs and lymphoid progenitors and is expressed by all of these stromal cell populations7,8,9,10,11. Here we selectively deletedCxcl12from candidate niche stromal cell populations and characterized the effect on HPCs. Deletion ofCxcl12from mineralizing osteoblasts has no effect on HSCs or lymphoid progenitors. Deletion ofCxcl12from osterix-expressing stromal cells, which include CXCL12-abundant reticular cells and osteoblasts, results in constitutive HPC mobilization and a loss of B-lymphoid progenitors, but HSC function is normal.Cxcl12deletion from endothelial cells results in a modest loss of long-term repopulating activity. Strikingly, deletion of Cxcl12from nestin-negative mesenchymal progenitors usingPrx1–cre(Prx1also known asPrrx1) is associated with a marked loss of HSCs, long-term repopulating activity, HSC quiescence and common lymphoid progenitors. These data suggest that osterix-expressing stromal cells comprise a distinct niche that supports B-lymphoid progenitors and retains HPCs in the bone marrow, and that expression of CXCL12 from stromal cells in the perivascular region, including endothelial cells and mesenchymal progenitors, supports HSCs.

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