Identification of the Hemogenic Endothelial Progenitor and Its Direct Precursor in Human Pluripotent Stem Cell Differentiation Cultures

• Published in: Cell reports (Cambridge) Vol. 2; no. 3; pp. 553 - 567
• Main Authors: Choi, Kyung-Dal, Vodyanik, Maxim A., Togarrati, Padma Priya, Suknuntha, Kran, Kumar, Akhilesh, Samarjeet, Fnu, Probasco, Mitchell D., Tian, Shulan, Stewart, Ron, Thomson, James A., Slukvin, Igor I.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 27.09.2012; Elsevier
• Subjects: Antigens, CD - metabolism; Cadherins - metabolism; Cell Differentiation - physiology; Cell Line; Fibroblast Growth Factor 2 - metabolism; Hemangioblasts - cytology; Hemangioblasts - metabolism; Hematopoietic Stem Cells - cytology; Hematopoietic Stem Cells - metabolism; Humans; Pluripotent Stem Cells - cytology; Pluripotent Stem Cells - metabolism
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2012.08.002

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 KDRbrightAPLNR+PDGFRαlow/− 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. [Display omitted] ► Definitive blood cells in human pluripotent stem cell cultures originate from hemogenic endothelium ► Hemogenic endothelium can be identified by a VE-cadherin+CD73−CD235a/CD43− phenotype ► Hemogenic endothelium arises from a KDRbrightAPLNR+PDGFRαlow/− mesodermal precursor In the embryo, hematopoietic stem cells are derived from hemogenic endothelium (HE). Slukvin and colleagues show that HE can be generated from human pluripotent stem cells and identified by a specific marker phenotype. Unlike mesodermal precursors with primitive hematopoietic potential, hemangioblasts, HE can generate definitive hematopoietic cells. The demarcation of HE allows the identification of molecular determinants of hematopoietic stem cell development, with the goal of developing novel stem-cell-based therapies.