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Blood, 1 November 2008, Vol. 112, No. 9, pp. 3601-3614.
Prepublished online as a Blood First Edition Paper on August 26, 2008September 5, 2008; DOI 10.1182/blood-2008-03-144766.
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Submitted March 11, 2008
Accepted June 23, 2008
Expression of ACE (CD143) identifies and regulates primitive hemangioblasts derived from human pluripotent stem cells
Elias T Zambidis*, Tea Soon Park, Wayne Yu, Ada Tam, Michal Levine, Xuan Yuan, Marina Pryzhkova, and Bruno Peault
Institute of Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, United States
Stem Cell Research Center, Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States
Division of Pediatric Oncology, Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, United States
* Corresponding author; email: ezambid1{at}jhmi.edu.
We report that angiotensin-converting enzyme (ACE), a critical physiologic regulator of blood pressure, angiogenesis, and inflammation, is a novel marker for identifying hemangioblasts from differentiating human embryonic stem cells (hESC). We demonstrate that ACE+CD45-CD34+/- hemangioblasts are common yolk sac (YS)-like progenitors for not only endothelium, but also both primitive and definitive human lympho-hematopoietic cells. Thrombopoietin and basic fibroblast growth factor are identified as critical factors for the proliferation of human hemangioblasts. The developmental sequence of human embryoid body (hEB) hematopoiesis is remarkably congruent to the timeline of normal human YS development, which occurs during weeks 2-6 of human gestation. Furthermore, ACE and the renin-angiotensin system (RAS) directly regulate hemangioblast expansion and differentiation, via signaling through the angiotensin II receptors, AGTR1 and AGTR2. ACE enzymatic activity is required for hemangioblast expansion, and differentiation toward either endothelium or multipotent hematopoietic progenitors is dramatically augmented following manipulation of angiotensin II signaling with either AGTR1- or AGTR2-specific inhibitors. The RAS can therefore be exploited to direct the hematopoietic or endothelial fate of hESC-derived hemangioblasts, thus providing novel opportunities for human tissue engineering. Moreover, the initial events of human hemato-endotheliogenesis can now be delineated in a manner that was previously impossible due to inaccessibility to human embryonic tissues.
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