Hematopoietic Stem Cell Niches Produce Lineage-Instructive Signals to Control Multipotent Progenitor Differentiation

Hematopoietic stem cells (HSCs) self-renew in bone marrow niches formed by mesenchymal progenitors and endothelial cells expressing the chemokine CXCL12, but whether a separate niche instructs multipotent progenitor (MPP) differentiation remains unclear. We show that MPPs resided in HSC niches, where they encountered lineage-instructive differentiation signals. Conditional deletion of the chemokine receptor CXCR4 in MPPs reduced differentiation into common lymphoid progenitors (CLPs), which decreased lymphopoiesis. CXCR4 was required for CLP positioning near Interleukin-7+ (IL-7) cells and for optimal IL-7 receptor signaling. IL-7+ cells expressed CXCL12 and the cytokine SCF, were mesenchymal progenitors capable of differentiation into osteoblasts and adipocytes, and comprised a minor subset of sinusoidal endothelial cells. Conditional Il7 deletion in mesenchymal progenitors reduced B-lineage committed CLPs, while conditional Cxcl12 or Scf deletion from IL-7+ cells reduced HSC and MPP numbers. Thus, HSC maintenance and multilineage differentiation are distinct cell lineage decisions that are both controlled by HSC niches. [Display omitted] •Hematopoietic multipotent progenitors require CXCR4 for multilineage differentiation•IL-7 acts as a short-range signal for common lymphoid progenitor differentiation•IL-7+ cells are CXCL12-abundant reticular mesenchymal progenitor cells•CXCL12 and SCF expressed by IL-7+ cells control the number of HSCs and MPPs in BM Hematopoietic stem cells reside in rare niches in bone marrow, where they are maintained throughout life, but where these cells differentiate remains unclear. Cordeiro Gomes et al. find that hematopoietic multipotent progenitor cells localize to hematopoietic stem cell niches in bone marrow, where they receive lineage-instructive differentiation signals.