VE-cadherin expression allows identification of a new class of hematopoietic stem cells within human embryonic liver

Abstract

Edification of the human hematopoietic system during development is characterized by the production of waves of hematopoietic cells separated in time, formed in distinct embryonic sites (ie, yolk sac, truncal arteries including the aorta, and placenta). The embryonic liver is a major hematopoietic organ wherein hematopoietic stem cells (HSCs) expand, and the future, adult-type, hematopoietic cell hierarchy becomes established. We report herein the identification of a new, transient, and rare cell population in the human embryonic liver, which coexpresses VE-cadherin, an endothelial marker, CD45, a pan-hematopoietic marker, and CD34, a common endothelial and hematopoietic marker. This population displays an outstanding selfrenewal, proliferation, and differentiation potential, as detected by in vitro and in vivo hematopoietic assays compared with its VE-cadherin negative counterpart. Based on VE-cadherin expression, our data demonstrate the existence of 2 phenotypically and functionally separable populations of multipotent HSCs in the human embryo, the VEcadherin ؉ one being more primitive than the VE-cadherin ؊ one, and shed a new light on the hierarchical organization of the embryonic liver HSC compartment.

Fusing VE-Cadherin to α-Catenin Impairs Fetal Liver Hematopoiesis and Lymph but Not Blood Vessel Formation

“…As HSPCs arise from hemogenic endothelium, they still weakly express VE-cadherin at their earliest differentiation stages (33,34). Therefore, we wanted to investigate a potential role of VE-cadherin during differentiation of HSPCs, which could be affected by VEC-␣-C. To this end, we conditionally deleted VE-cadherin by crossing VE-cadherin conditional knockout mice (Cdh5 fl/fl ) to Vav-iCre mice (Vav-iCre ϩ/T ) that express Cre under an early hematopoietic promoter (21,35).…”

“…The few HSPCs that succeeded in entering the fetal liver had a normal capacity to proliferate and differentiate. Since Vav-iCre-driven deletion of VEcadherin in HSPCs did not result in hematopoietic abnormalities, we excluded that low-level VE-cadherin described on the earliest hematopoietic populations (33,34) was relevant for fetal liver colonization. Thus, stabilization of endothelial junctions via the VEC-␣-C fusion does not affect the generation or differentiation of hematopoietic cells but appears to inhibit transendothelial migration of HSPCs into the fetal liver.…”

Notch1 controls development of the extravillous trophoblast lineage in the human placenta

“…However, the stemness markers myc, markedly decreasing during the first trimester of pregnancy (52), and VE-cadherin, were mainly detected in CCTs. Besides its classical role in endothelial cells, VE-cadherin also specifies a transient, hematopoetic stem cell population in the developing liver (53). In anchoring villi VE-cadherin specifically localizes to the intermediate region of the cell column containing proliferative CCT (Fig.…”

Human haematopoietic stem cell development: from the embryo to the dish

“…In general, repopulation with yolk sac cells was significantly rarer than with AGM region cells. A robust presence of HSCs in the liver is generally detected later, from week 7-8 and the most potent subset of liver HSCs still express VE-cadherin, reflecting their endothelial origin (Oberlin et al, 2010;Ivanovs et al, 2011). Although the appearance of HSCs in the mouse AGM region, yolk sac, umbilical cord, liver and placenta occur almost concurrently (Müller et al, 1994;de Bruijn et al, 2000;Kumaravelu et al, 2002;Gekas et al, 2005;Ottersbach and Dzierzak, 2005), their appearance in different locations in human embryo is temporally resolved, owing to a more protracted developmental period.…”