Inducible Forward Programming of Human Pluripotent Stem Cells to Hemato-endothelial Progenitor Cells with Hematopoietic Progenitor Potential

Induced pluripotent stem cells (iPSCs) offer a promising platform to model early embryonic developmental processes, to create disease models that can be evaluated by drug screens as well as proof-of-concept experiments for regenerative medicine. However, generation of iPSC-derived hemato-endothelial and hematopoietic progenitor cells for these applications is challenging due to variable and limited cell numbers, which necessitates enormous up-scaling or development of demanding protocols. Here, we unravel the function of key transcriptional regulators SCL, LMO2, GATA2, and ETV2 (SLGE) on early hemato-endothelial specification and establish a fully inducible and stepwise hemato-endothelial forward programming system based on SLGE-regulated overexpression. Regulated induction of SLGE in stable SLGE-iPSC lines drives very efficient generation of large numbers of hemato-endothelial progenitor cells (CD144(+)/CD73(–)), which produce hematopoietic progenitor cells (CD45(+)/CD34(+)/CD38(–)/CD45RA(−)/CD90(+)/CD49f(+)) through a gradual process of endothelial-to-hematopoietic transition (EHT).