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The successful derivation of human embryonic stem cells (hESCs) in 1998 (1) and later of induced pluripotent stem cells (iPSCs) in 2006/2007 (2, 3) led to huge excitement and held great promise to revolutionize several fields, from basic research to regenerative and personalized medicine, as these human pluripotent cells (hPSCs) have the potential when cultured under the right conditions to give rise to every lineage, tissue, and cell of the human body. Given the unique source and properties of these cells, the research as well as clinical uses of hESCs and iPSCs were, however, from the beginning met with a common and a unique set of ethical and safeguarding issues, which are still being hotly debated (4⇓–6). Moreover, protocols for efficient differentiation of hPSCs into the desired tissues and cell types still need substantial optimizations for efficient and safe clinical uses. As a result, despite the enthusiasm and intensive research activities, the clinical application of hPSCs is still in its early phases and needs to overcome various obstacles for its full potential (4⇓–6). One of the major bottlenecks for its hematopoietic application is the (ex vivo) generation of functional human hematopoietic stem/progenitor cells (HSPCs) with long-term repopulating capacity and multilineage differentiation potential (7, 8). Not until recently has a protocol for in vivo respecification of iHSPCs been reported (9), where hESCs were subjected to morphogen-directed differentiation into hemogenic endothelium (HE), which then were cultured under endothelial-to-hematopoietic transition conditions followed by transient expression of seven transcription factors (ERG, HOXA5, HOXA9, HOXA10, LCOR, RUNX1, and SPI1). Upon transplantation, long-term and transplantable multilineage (B, T, and myeloid cells) engraftment was observed, albeit with notable B cell bias (Fig. 1) (9). Despite the requirement of an intermediate cell state and expression of multiple factors, this study … [↵][1]1To whom correspondence should be addressed. Email: eric.so{at}kcl.ac.uk. [1]: #xref-corresp-1-1