Abstract Mouse hematopoietic stem cells (HSCs) first emerge at embryonic day 10.5 (E10.5) on the ventral surface of the dorsal aorta, by endothelial-to-hematopoietic transition (EHT). We investigated whether cells with mesenchymal stem cell-like activity, which provide an essential niche for long-term HSCs (LT-HSCs) in the bone marrow, reside in the aorta- gonad-mesonephros (AGM) and contribute to the structural development of the dorsal aorta and EHT. Using transgenic mice, we demonstrate a lineage hierarchy for AGM stromal cells and traced the E10.5/E11.5 aortic endothelium and HSCs to mesoderm derived ( Mesp1 ) PDGFRA + stromal cells ( Mesp1 der PSCs). Mesp1 der PSCs dominate the sub-endothelial and ventral stroma in the E10.5–E11.5 AGM but by E13.5 were replaced by neural crest ( Wnt1 ) derived PDGFRA + stromal cells ( Wnt1 der PSCs). Co-aggregating non-hemogenic embryonic and adult endothelial cells with Mesp1 der PSCs but not with Wnt1 der PSCs resulted in activation of a hematopoietic transcriptional program in endothelial cells accompanied by EHT and generation of LT-HSCs. Dose-dependent inhibition of PDGFRA signalling or BMP, WNT, NOTCH signalling interrupted this reprogramming event. This partnership between endothelial cells and AGM Mesp1 der PSCs could potentially be harnessed to manufacture LT-HSCs from endothelium.

Mesoderm-Derived PDGFRA+Cells Regulate the Emergence of Hematopoietic Stem Cells in the Dorsal Aorta