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Significance We designed this study to evaluate the feasibility of using only one factor to respecify human induced pluripotent stem cell (iPSC)-derived blood cells into long-term engraftable hematopoietic stem and progenitor cells (HSPCs). By transiently expressing a single transcription factor, MLL-AF4, the iPSC-derived blood cells could gain robust engraftability with multilineage reconstitution potential. Myeloid differentiation bias has been considered a big barrier for deriving functional HSPCs from human iPSCs, and we showed thatMLL-AF4– induced HSPCs (iHSPCs) were able to reestablish both myelopoiesis and lymphopoiesis without lineage bias in the recipient mice. By parallell comparison of iHSPCs withMLL-AF4 –induced primary HSPCs, we also found that iHSPCs were more prone to leukemic transformation during the long-term engraftment period, which provided a necessary caveat of using iHSPCs in the actual therapies.

Respecifying human iPSC-derived blood cells into highly engraftable hematopoietic stem and progenitor cells with a single factor