Definitive human and mouse hematopoiesis originates from the embryonic endothelium: a new class of HSCs based on VE-cadherin expression

Abstract

Hematopoietic stem cells (HSCs) arise first in the third week of human ontogeny inside yolk sac developing blood vessels, and independently, from the wall of the embryonic aorta and vitelline arteries one week later. HSCs produced in the yolk sac and in the embryonic truncal arteries migrate to and transiently colonize the embryonic liver (EL), and thereafter the bone marrow (BM), their permanent site of residence. At the moment, the origin of human HSCs is still controversial; one of the main hypotheses being that they are generated by hemogenic endothelial cells (ECs). To proove definitively the endothelial origin of HSCs that arise within the human embryo, we previously purified ECs from either the yolk sac or the truncal arteries and reported that they were able to produce blood cells in vitro. We then found that some of the HSCs present in the human EL were co-expressing vascular endothelial (VE)-cadherin, an endothelial marker, CD45, a pan-hematopoietic marker, and CD34, a common endothelial and hematopoietic marker, and demonstrated that these HSCs bearing a dual hemato-endothelial phenotype were endowed with remarkably high self renewal and proliferative potentials. Furthermore, a transgenic mouse model based on the VE-cadherin cis-regulating elements that we engineered to trace the fate of the first VE-cadherin expressing cells allowed us to clearly demonstrate that a majority of adult BM HSCs derived from a VE-cadherin ancestor. Altogether our studies strongly suggest that at least a part of both the human and the murine hematopoietic systems arise from an endotheliumlike ancestor.

Endothelial cell and podocyte autophagy synergistically protect from diabetes-induced glomerulosclerosis

“…6A). 57 We also crossed the Cdh5.Cre strain with a ROSA26R-LacZ reporter line (Table S1) and found b-galactosidase staining in most, but not all (around 75%), of the glomerular endothelial cells and in interstitial capillaries in the kidneys of Cdh5.Cre ROSA26R-LacZ mice (Fig. S5A).…”

“…55 Mice with an endothelial-specific disruption of the Atg5 gene (Cdh5.Cre-atg5 lox/lox ) were generated by crossing Cdh5.Cre mice 57 with Atg5 lox/lox mice. 55 Mice were bred on pure C57BL/6J genetic background.…”

CD45 Expression in Mitral Valve Endothelial Cells After Myocardial Infarction

“…An exception is during embryonic development when specific sites within the yolk sac, the placenta and the dorsal aorta become “hemogenic” for a narrow window of time. CD45+/VE-cadherin+ cells bud from the hemogenic endothelium to give rise to hematopoietic stem cells 41, 42 . Purified cultures of human endothelial cells are typically devoid of CD45+ cells 43 , although we detected a limited window of hemogenic activity in human umbilical cord blood CD133-selected endothelial colony forming cells 44 .…”

Hematopoietic Stem Cell Development, Niches, and Signaling Pathways

“…Recently, this evidence has been supported by the observation on time-lapse confocal imaging from live mouse aorta showing that HSCs (Sca + , c-kit + , CD41 + ) could emerge directly from ventral aortic endothelial cells [46]. Moreover, Oberlin and colleagues proved that the origin of adult bone marrow HSCs which most of them derived were from the vascular endothelial-cadherin ancestor [47]. Taken together, these studies pinpoint the evidence that definitive hematopoietic stem and progenitor cells emerge from the hemogenic endothelium at the AGM region.…”