Renin‐angiotensin system is involved in embryonic emergence of hematopoietic stem/progenitor cells

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. All renin‐angiotensin system (RAS) components required for bioactive angiotensin II (Ang II) ‐synthesis and ‐signaling (Ang II type 1 [AT1] receptors) are synthesized locally in the aorta‐gonad‐mesonephros region of the developing mouse embryo, supporting the existence of a local dynamic RAS that directly/indirectly promotes the emergence of hematopoietic progenitor cells by stimulating the proliferation/migration of pre‐hematopoietic precursor cells localized in the subluminal aortic layers which then integrate the endothelial hemogenic layer.