The continuous generation of blood cells throughout life relies on the existence of hematopoietic stem cells (HSC) generated during embryogenesis. Given the importance of HSC transplantation in cell-based therapeutic approaches, considerable efforts have been made toward understanding the developmental origins of embryonic HSC. Adult-type HSC are first generated in the aorta-gonad-mesonephros (AGM) region between days 27 and 40 of human embryonic development, but an elusive blood-forming potential is present earlier in the underlying splanchnopleura. It is relatively well accepted that the HSC emerge in the AGM through a hemogenic endothelium, but the direct precursor of this cell type remains to be clearly identified. This review is intended to summarize the recent advances made to understand the origins of hematopoietic stem cells in the early human embryo. In addition, we discuss in detail the discovery of the angiotensin-converting enzyme (ACE) as a novel marker of human HSC and of prehematopoietic precursors inside the embryo.

Angiotensin‐converting enzyme (ACE), a key element of the renin‐angiotensin system (RAS), has recently been identified as a new marker of both adult and embryonic human hematopoietic stem/progenitor cells (HSPCs). However, whether a full renin‐angiotensin pathway is locally present during the hematopoietic emergence is still an open question. In the present study, we show that this enzyme is expressed by hematopoietic progenitors in the developing mouse embryo. Furthermore, ACE and the other elements of RAS—namely angiotensinogen, renin, and angiotensin II type 1 (AT1) and type 2 (AT2) receptors—are expressed in the paraaortic splanchnopleura (P‐Sp) and in its derivative, the aorta‐gonad‐mesonephros region, both in human and mouse embryos. Their localization is compatible with the existence of a local autocrine and/or paracrine RAS in these hemogenic sites. in vitro perturbation of the RAS by administration of a specific AT1 receptor antagonist inhibits almost totally the generation of blood CD45‐positive cells from dissected P‐Sp, implying that angiotensin II signaling is necessary for the emergence of hematopoietic cells. Conversely, addition of exogenous angiotensin II peptide stimulates hematopoiesis in culture, with an increase in the number of immature c‐Kit+CD41+CD31+CD45+ hematopoietic progenitors, compared to the control. These results highlight a novel role of local‐RAS during embryogenesis, suggesting that angiotensin II, via activation of AT1 receptor, promotes the emergence of undifferentiated hematopoietic progenitors.

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Key Points Expression of caudal-related homeobox gene 2 (CDX2) and angiotensin-converting enzyme (ACE) correlates during hematopoietic emergence. This emergence occurs in human and mouse embryos and in human acute myeloid leukemia; CDX2 homeoprotein also binds to the ACE promoter.