show Abstracthide AbstractAdvancing pluripotent stem cell technologies for modeling hematopoietic stem cell development and therapies requires identifying key regulators of hematopoietic commitment from human pluripotent stem cells (hPSCs). Here, by screening the effect of 27 candidate factors, we identified two groups of transcriptional regulators capable of inducing distinct hematopoietic programs from hPSCs: pan-myeloid (GATA2 and ETV2) and erythro-megakaryocytic (GATA2 and TAL1). In both cases, these transcription factors directly converted hPSCs to endothelium, which subsequently transformed into blood cells with pan-myeloid or eryhtro-megakaryocytic potential. These data demonstrate that two distinct genetic programs regulate the hematopoietic development from hPSCs and that both of these programs specify hPSCs directly to hemogenic endothelial cells. Additionally, this study provides a novel method for efficient induction of blood and endothelial cells from hPSCs via overexpression of modified mRNA for selected transcription factors. Overall design: mRNA profiles of 54 samples, including 4 samples in duplicate and 6 control samples were generated by deep sequencing, using Illumina HiSeq 2500.