Circulation-Independent Differentiation Pathway from Extraembryonic Mesoderm toward Hematopoietic Stem Cells via Hemogenic Angioblasts

A large gap exists in our understanding of the course of differentiation from mesoderm to definitive hematopoietic stem cells (HSCs). Previously, we reported that Runx1+ cells in embryonic day 7.5 (E7.5) embryos contribute to the hemogenic endothelium in the E10.5 aorta-gonad-mesonephros (AGM) region and HSCs in the adult bone marrow. Here, we show that two Runx1+ populations subdivided by Gata1 expression exist in E7.5 embryos. The hemogenic endothelium and the HSCs are derived only from the Runx1+Gata1− population. A subset of this population moves from the extra- to intraembryonic region during E7.5–E8.0, where it contributes to the hemogenic endothelium of the dorsal aorta (DA). Migration occurs before the heartbeat is initiated, and it is independent of circulation. This suggests a developmental trajectory from Runx1+ cells in the E7.5 extraembryonic region to definitive HSCs via the hemogenic endothelium. [Display omitted] •Two Runx1+ populations subdivided by Gata1 expression exist in E7.5 embryos•E7.5 Runx1+Gata1− cells (R+G− cells) contribute to HSC lineage and endothelium•E7.5 R+G− cells migrate from extra- to intraembryonic site at precirculation stage•E7.5 R+G− cells that contribute to intraembryonic endothelium have hemogenic potential Hematopoietic stem cells (HSCs) from embryonic day 10.5 (E10.5) hemogenic endothelium appear in various tissues, such as the aorta-gonad-mesonephros, yolk sac, placenta, vitelline vessels, and umbilical vessels. However, the origin of the hemogenic endothelium remains unknown. Here, Tanaka et al. demonstrate that E7.5 Runx1+Gata1− extraembryonic cells contribute to the hemogenic endothelium in these tissues as well as HSCs. The authors also show that E7.5 Runx1+Gata1− extraembryonic cells migrate into the intraembryonic region and then contribute to the intraembryonic hemogenic endothelium prior to circulation.