Haematopoietic stem cells derive directly from aortic endothelium during development

In zebrafish, haematopoietic stem cells (HSCs) arise from the dorsal aorta of the embryo. In vitro studies have suggested that there are in the dorsal aorta a population of intermediate progenitors that can give rise to both endothelial (or blood vessel lineage) and blood cells. In this issue, two groups present images showing the birth of HSCs from the ventral wall of the dorsal aorta in live zebrafish embryos. Bertrand et al. combined fluorescent reporter transgenes, confocal time-lapse microscopy and flow cytometry to identify and isolate the stepwise intermediates as aortic haemogenic endothelium transitions to nascent HSCs. They also show that the HSCs generated from this haemogenic endothelium are the lineal founders of virtually all of the adult haematopoietic system. Karima Kissa and Philippe Herbomel similarly use imaging of live zebrafish to show HSCs emerge directly from the aorta floor, They show this process that does not involve cell division but movement of single endothelial cells out of the aorta ventral wall into the sub-aortic space, where they transform into haematopoietic cells. They call this new type of cell behaviour endothelial haematopoietic transition (EHT). In a third report, Boisset et al. confirm that this process also occurs in mice, using a dissection procedure to visualize the deeply located aorta. They showed de novo emergence of phenotypically defined HSCs directly from ventral aortic haemogenic endothelial cells. One of two papers showing the generation of haematopoietic stem cells (HSCs) from the ventral wall of the dorsal aorta in live zebrafish embryos. Here, combined fluorescent reporter transgenes, confocal time-lapse microscopy and flow cytometry identify and isolate the stepwise intermediates as aortic haemogenic endothelium transitions to nascent HSCs. HSCs generated from this haemogenic endothelium are the lineal founders of virtually all of the adult haematopoietic system. A major goal of regenerative medicine is to instruct formation of multipotent, tissue-specific stem cells from induced pluripotent stem cells (iPSCs) for cell replacement therapies. Generation of haematopoietic stem cells (HSCs) from iPSCs or embryonic stem cells (ESCs) is not currently possible, however, necessitating a better understanding of how HSCs normally arise during embryonic development. We previously showed that haematopoiesis occurs through four distinct waves during zebrafish development, with HSCs arising in the final wave in close association with the dorsal aorta. Recent reports have suggested that murine HSCs derive from haemogenic endothelial cells (ECs) lining the aortic floor1,2. Additional in vitro studies have similarly indicated that the haematopoietic progeny of ESCs arise through intermediates with endothelial potential3,4. Here we have used the unique strengths of the zebrafish embryo to image directly the generation of HSCs from the ventral wall of the dorsal aorta. Using combinations of fluorescent reporter transgenes, confocal time-lapse microscopy and flow cytometry, we have identified and isolated the stepwise intermediates as aortic haemogenic endothelium transitions to nascent HSCs. Finally, using a permanent lineage tracing strategy, we demonstrate that the HSCs generated from haemogenic endothelium are the lineal founders of the adult haematopoietic system.