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The intrinsic factors that determine the fundamental traits of engraftment ability and multi-lineage potential of hematopoietic stem cells (HSCs) remain elusive. The induction of bona fade HSCs from pluripotent stem cells (PSCs) in dishes is urgently demanded but remains a great challenge in translational medicine.  Runx1 ,  Hoxa9 ,  Hlf , and  Hoxa7  are developmentally co-expressed during endothelial-to-hematopoietic transition and adult haematopoiesis. However, the expression of these factors fails to be turned on during  in vitro  hematopoietic induction from PSCs. Here, we established an inducible gene over-expression embryonic stem cell (ESC) line in which exogenous  Runx1 ,  Hoxa9 ,  Hlf , and  Hoxa7  genes were tandemly knocked in. A population of induced hematopoietic progenitor cells (iHPCs) expressing Kit and Sca1 surface markers were successfully obtained  in vitro  from the gene edited-ESC line. Upon transplantation of the  Runx1-Hoxa9-Hlf-Hoxa7  ESC-derived iHPCs into irradiated immunodeficient mice, they can dominantly contribute to B cells, low proportions of T cells and myeloid cells. However,  Runx1 - Hoxa9 - Hlf  ESC-derived iHPCs only produced B lineage cells with extremely low contributions. Our study unveils that the coordination of  Runx1 ,  Hoxa9 ,  Hlf , and  Hoxa7  led to generation of the hematopoietic progenitors with the capacity of multi-lineage hematopoietic reconstitution in the immunodeficient recipient mice.

Co-Expression of Runx1, Hoxa9, Hlf, and Hoxa7 Confers Multi-Lineage Potential on Hematopoietic Progenitors Derived From Pluripotent Stem Cells