Abstract
Hemogenic endothelium (HE) has been recognized as a source of hematopoietic stem cells (HSCs) in the embryo. Access to human HE progenitors (HEPs) is essential for enabling the investigation of the molecular determinants of HSC specification. Here, we show that HEPs capable of generating definitive hematopoietic cells can be obtained from human pluripotent stem cells (hPSCs) and identified precisely by a VE-cadherin(+)CD73(-)CD235a/CD43(-) phenotype. This phenotype discriminates true HEPs from VE-cadherin(+)CD73(+) non-HEPs and VE-cadherin(+)CD235a(+)CD41a(-) early hematopoietic cells with endothelial and FGF2-dependent hematopoietic colony-forming potential. We found that HEPs arise at the post-primitive-streak stage of differentiation directly from VE-cadherin-negative KDR(bright)APLNR(+)PDGFRα(low/-) hematovascular mesodermal precursors (HVMPs). In contrast, hemangioblasts, which are capable of forming endothelium and primitive blood cells, originate from more immature APLNR(+)PDGFRα(+) mesoderm. The demarcation of HEPs and HVMPs provides a platform for modeling blood development from endothelium with a goal of facilitating the generation of HSCs from hPSCs.
Highlights
Establishing a system for de novo generation of hematopoietic stem cells (HSCs) from human pluripotent stem cells would open a unique opportunity to study human HSC development and provide a novel source of therapeutic cells for blood disease
We showed that hemogenic endothelium (HE) progenitors (HEPs) can be generated from human pluripotent stem cells (hPSCs) and be identified precisely based on VE-cadherin (CD144) expression but the lack of CD73 and CD235a/CD43 expression
Identification of functionally distinct progenitors with hematopoietic and/or endothelial potential within emerging embryonic VE-cadherin+ cells based on expression of CD73 and CD235a
Summary
Establishing a system for de novo generation of hematopoietic stem cells (HSCs) from human pluripotent stem cells (hPSCs) would open a unique opportunity to study human HSC development and provide a novel source of therapeutic cells for blood disease. Mouse and human embryonic studies demonstrated that definitive HSCs which give rise to all lineages of an adult hematopoietic system, are generated in the aorta-gonadmesonephros (AGM) region and are located at the ventral aspect of the dorsal aorta (de Bruijn et al, 2002; Ivanovs et al, 2011; Pardanaud et al, 1996; Taoudi and Medvinsky, 2007) In this area, hematopoietic cells arise from a unique population of endothelial cells known as hemogenic endothelium (HE) through an endothelial-hematopoietic transition (EHT) (Boisset et al, 2010; Jaffredo et al, 2000; Zovein et al, 2008). The concept of HE was coined based on observations of blood formation within the aorta, it is known that endothelium lining nascent capillaries in the yolk sac (Ferkowicz et al, 2003) and possibly vitelline and umbilical arteries (Yokomizo and Dzierzak, 2010) have the capacity to generate blood as well
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