We report that angiotensin-converting enzyme (ACE), a critical physiologic regulator of blood pressure, angiogenesis, and Inflammation, Is a novel marker for identifying hemangioblasts differentiating from human embryonic stem cells (hESC). We demonstrate that ACE+CD45-CD34 +/- hemangloblasts are common yolk sac (YS)-like progenitors for not only endothelium but also both primitive and definitive human lymphohematopoietic cells. Thrombopoletin and basic fibroblast growth factor are identified as critical factors for the proliferation of human hemangioblasts. The developmental sequence of human embryoid body hematopoiesis is remarkably congruent to the timeline of normal human YS development, which occurs during weeks 2 to 6 of human gestation. Furthermore, ACE and the reninangiotensin system (RAS) directly regulate hemangioblast expansion and differentiation via signaling through the angiotensin II receptors AQTR1 and AGTR2. ACE enzymatic activity is required for hemangioblast expansion, and differentiation toward either endothelium or multipotent hematopoietic progenitors is dramatically augmented after manipulation of angiotensin Il signaling with either AGTR1- or AGTR2-specific Inhibitors. The RAS can therefore be exploited to direct the hematopoietic or endothelial fate of hESC-derlved hemangioblasts, thus providing novel opportunities for human tissue engineering. Moreover, the initial events of human hematoendothellogenesis can be delineated In a manner previously Impossible because of inaccessibility to early human embryonic tissues.
ASJC Scopus subject areas
- Cell Biology