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 (Mesp1der PSCs). Mesp1der 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 (Wnt1der PSCs). Co-aggregating non-hemogenic embryonic and adult endothelial cells with Mesp1der PSCs but not with Wnt1der 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 Mesp1der PSCs could potentially be harnessed to manufacture LT-HSCs from endothelium.