Abstract
AbstractThe study of developmental hematopoiesis has provided important insights into the molecules that establish and sustain this process throughout adult life. At the base of the hematopoietic hierarchy is the hematopoietic stem cell (HSC), which emerges in the mouse conceptus starting at 10.5 days post coitus (≥ 34 somite pair stages).1 HSCs have been found in several distinct sites: the yolk sac, umbilical and vitelline arteries, the dorsal aorta in the aorta/gonad/mesonephros (AGM) region, fetal liver, and, more recently, the placenta.1–4 HSCs emerge from these sites (yolk sac, umbilical and vitelline arteries, and AGM region) through the formation of intra-aortic hematopoietic clusters that develop from endothelium.5–7 Studies in mouse, zebrafish, chick, and frog embryos established that Runx1 (AML1) is the earliest specific marker of all definitive hematopoietic sites in the conceptus. Runx1 is expressed in endothelial and mesenchymal cells and in intraaortic hematopoietic clusters, and marks all committed HPs and HSCs in both the embryo and the adult.6,8–10 It has been proposed that Runx1 functions during the transition from a “hemogenic endothelium” to intra-aortic clusters and HSCs.8 Here, we show that deletion of Runx1 in vascular endothelial cadherin (VEC) positive cells blocks the emergence of intra-aortic hematopoietic clusters, HPs, and HSCs. Greater than 95% of adult bone marrow cells are marked when VEC-Cre is used to delete a Rosa26 reporter allele, demonstrating that almost all blood cells have transited through a VEC+ intermediate at some point in their life. On the other hand, Runx1 deletion with Vav-Cre, which occurs in fetal liver HPs and HSCs, does not block hematopoiesis. Collectively, these data demonstrate that Runx1 is absolutely required in endothelial cells for hematopoietic cluster, HP, and HSC formation, but after HSCs are born from endothelium, Runx1 is no longer required to maintain them.
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