Restricted Hematopoietic Progenitors and Erythropoiesis Require SCF from Leptin Receptor+ Niche Cells in the Bone Marrow

Abstract

Hematopoietic stem cells (HSCs) are maintained in a perivascular niche in bone marrow, in which leptin receptor + (LepR) stromal cells and endothelial cells synthesize factors required for HSC maintenance, including stem cell factor (SCF). An important question is why LepR + cells are one hundred times more frequent than HSCs. Here, we show that SCF from LepR + cells is also necessary to maintain many c-kit + -restricted hematopoietic progenitors. Conditional deletion of Scf from LepR + cells depleted common myeloid progenitors (CMPs), common lymphoid progenitors (CLPs), granulocyte-macrophage progenitors (GMPs), megakaryocyte-erythrocyte progenitors (MEPs), pre-megakaryocyte-erythrocyte progenitors (PreMegEs), and colony-forming units-erythroid (CFU-Es), as well as myeloid and erythroid blood cells. This was not caused by HSC depletion, as many other restricted progenitors were unaffected. Moreover, Scf deletion from endothelial cells depleted HSCs, but not progenitors. Early erythroid progenitors were closely associated with perisinusoidal LepR + cells. This reveals cellular specialization within the niche: SCF from LepR + cells is broadly required by HSCs and restricted progenitors while SCF from endothelial cells is required mainly by HSCs. Bone marrow hematopoietic stem cells reside in perivascular niches associated with sinusoids and require factors from leptin receptor + stromal cells and endothelial cells. Morrison and colleagues show that c-kit + -restricted hematopoietic progenitors also require Stem Cell Factor made by LepR + cells, but not endothelial cells. At least some of these restricted progenitors reside in perisinusoidal niches.