Endothelio-Mesenchymal Interaction Controls runx1 Expression and Modulates the notch Pathway to Initiate Aortic Hematopoiesis

Hematopoietic stem cells (HSCs) are produced by a small cohort of hemogenic endothelial cells (ECs) during development through the formation of intra-aortic hematopoietic cell (HC) clusters. The Runx1 transcription factor plays a key role in the EC-to-HC and -HSC transition. We show that Runx1 expression in hemogenic ECs and the subsequent initiation of HC formation are tightly controlled by the subaortic mesenchyme, although the mesenchyme is not a source of HCs. Runx1 and Notch signaling are involved in this process, with Notch signaling decreasing with time in HCs. Inhibiting Notch signaling readily increases HC production in mouse and chicken embryos. In the mouse, however, this increase is transient. Collectively, we show complementary roles of hemogenic ECs and mesenchymal compartments in triggering aortic hematopoiesis. The subaortic mesenchyme induces Runx1 expression in hemogenic-primed ECs and collaborates with Notch dynamics to control aortic hematopoiesis. ► The subaortic mesenchyme controls endothelial Runx1 expression ► Notch signaling is critical for the endothelial-to-hematopoietic transition ► Decrease of Notch signaling is necessary to generate aortic hematopoiesis Richard et al. show that the subaortic mesenchyme induces Runx1 expression in hemogenic-primed aortic endothelial cells. A decrease of endothelial Notch signaling increases Runx1 expression and promotes aortic hematopoiesis. This study shows complementary roles of hemogenic endothelium and mesenchymal compartments in triggering aortic hematopoiesis by modulating the Notch-Runx1 pathway.