Hematopoietic stem cell niches control multipotent progenitor differentiation

Hematopoietic stem cells (HSC) self-renew in bone marrow niches formed by CXCL12 + mesenchymal progenitor and endothelial cells. Here, we show that hematopoietic multipotent progenitors (MPPs) encounter lineage-instructive differentiation signals in HSC niches. Conditional deletion of CXCR4 in MPPs profoundly reduced differentiation into common lymphoid progenitors (CLPs), which significantly decreased lymphopoiesis. CXCR4 was required for CLP positioning near IL-7 + cells and, consequently, for optimal IL-7R signaling. IL-7 + cells form a large subset of CXCL12-abundant reticular mesenchymal progenitor cells capable of differentiation into osteoblasts and adipocytes, and a minor subset of BM sinusoidal endothelial cells. Conditional Il7 deletion in Lepr+ mesenchymal progenitor cells dramatically reduced B-lineage committed CLPs, developing B cell subsets, and peripheral mature B cells. Importantly, more than 50% of HSCs and MPPs were found in direct contact with IL-7+ cells, and more than 75% of HSCs and MPPs resided at + mesenchymal progenitors. We conclude that HSC maintenance and multilineage differentiation are distinct cell lineage decisions controlled by HSC niches.