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

2013; Nature Portfolio; Volume: 495; Issue: 7440 Linguagem: Inglês

10.1038/nature11926

1476-4687

Adam Greenbaum, Yen‐Michael S. Hsu, Ryan B. Day, Laura G. Schuettpelz, Matthew Christopher, Joshua N. Borgerding, Takashi Nagasawa, Daniel C. Link,

Immunotherapy and Immune Responses

Targeted deletion of the chemokine Cxcl12 in different bone marrow stromal cell populations shows that distinct niches exist in the bone marrow for haematopoietic stem cells and lineage-committed progenitors. The chemokine CXCL12 has an important role in maintaining haematopoietic stem cell (HSC) function. Two complementary papers in the issue of Nature study the effects of conditional deletion of Cxcl12 from candidate niche cells in the bone marrow and arrive at similar conclusions despite using different cre and Cxcl12 alleles. Lei Ding and Sean Morrison map CXCL12 expression in different (putative) niche components of the adult mouse bone marrow, showing that deletion of Cxcl12 from endothelial cells, but not Lepr–cre-targeted perivascular stromal cells, contributes to HSC maintenance. These niches do not overlap, indicating compartmentalization in the bone marrow microenvironment. Daniel Link and colleagues deleted Cxcl12 from candidate niche stromal cell populations and found that expression of CXCL12 from osterix-expressing stromal cells supports B-lymphoid progenitors and retains haematopoietic progenitor cells in the bone marrow, whereas its expression from stromal cells in the perivascular region supports HSCs. These insights into the complexity of the HSC niche are of relevance to work on the development of haematopoietic disease. Haematopoietic stem cells (HSCs) primarily reside in the bone marrow where signals generated by stromal cells regulate their self-renewal, proliferation and trafficking. Endosteal osteoblasts1,2 and perivascular stromal cells including endothelial cells3, CXCL12-abundant reticular cells4,5, leptin-receptor-positive stromal cells6, and nestin–green fluorescent protein (GFP)-positive mesenchymal progenitors7 have 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 deleted Cxcl12 from candidate niche stromal cell populations and characterized the effect on HPCs. Deletion of Cxcl12 from mineralizing osteoblasts has no effect on HSCs or lymphoid progenitors. Deletion of Cxcl12 from 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. Cxcl12 deletion from endothelial cells results in a modest loss of long-term repopulating activity. Strikingly, deletion of Cxcl12 from nestin-negative mesenchymal progenitors using Prx1–cre (Prx1 also known as Prrx1) 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.