Foxc1 is a critical regulator of haematopoietic stem/progenitor cell niche formation

Haematopoietic stemand progenitor cells are maintained by special microenvironments known as niches in bonemarrow1-6.Manystudies have identified diverse candidate cells that constitute niches for haematopoietic stem cells in the marrow, including osteoblasts^7-10, endothelial cells ^11-14, Schwanncells15,a-smoothmuscle actin-expressing macrophages¹⁶ and mesenchymal progenitors such as CXC chemokine ligand (CXCL)12-abundant reticular (CAR) cells1^7,18, stemcell factor-expressing cells13, nestin-expressing cells19 and platelet-derived growth factor receptor-α (PDGFR-α)⁺Sca-1 ⁺CD452Ter119^- (PaS) cells²⁰. However, the molecular basis of the formation of the niches remains unclear. Here we find that the transcription factor Foxc1 is preferentially expressed in the adipo-osteogenic progenitor CAR cells essential for haematopoietic stemand progenitor cell maintenance in vivo^5,13,18 in the developing and adult bone marrow. When Foxc1 was deleted in all marrow mesenchymal cells or CAR cells, fromembryogenesisonwards, osteoblasts appearednormal,but haematopoietic stem and progenitor cells were markedly reduced and marrow cavities were occupied by adipocytes (yellow adipose marrow) with reduced CAR cells. Inducible deletion of Foxc1 in adult mice depleted haematopoietic stemand progenitor cells and reduced CXCL12 and stem cell factor expression in CAR cells but did not induce a change to yellow marrow. These data suggest a role for Foxc1 in inhibiting adipogenic processes inCAR progenitors. Foxc1 might also promote CAR cell development, upregulating CXCL12 and stem cell factor expression. This study identifies Foxc1 as a specific transcriptional regulator essential for development and maintenance of the mesenchymal niches for haematopoietic stem and progenitor cells.