Expression of angiotensin-converting enzyme (CD143) identifies and regulates primitive hemangioblasts derived from human pluripotent stem cells

Institute of Cell Engineering, Stem Cell Program, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Blood (Impact Factor: 10.45). 10/2008; 112(9):3601-14. DOI: 10.1182/blood-2008-03-144766
Source: PubMed


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+/- hemangioblasts are common yolk sac (YS)-like progenitors for not only endothelium but also both primitive and definitive human lymphohematopoietic 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 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 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 after 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 hematoendotheliogenesis can be delineated in a manner previously impossible because of inaccessibility to early human embryonic tissues.

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    • "Human embryonic stem cell-derived ACE+CD45-CD34+/- cells are the common yolk sac-like progenitors for not only the endothelium, but also for both primitive and definitive human lymphohematopoietic stem cells [26]. Human angiohematopoiesis initiates from an ACE-hemangioblastic progenitor of primitive and definitive hematopoiesis under the functional activities of the local RAS [26]. Sinka et al. [24] searched for the presence of ACE in the earliest pre-aorta-gonad-mesonephros stages of human intraembryonic angiohematopoiesis. "
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    ABSTRACT: Objective: The prominent functions of the local renin-angiotensin system (RAS) in primitive hematopoiesis further support the hypothesis that local autocrine bone marrow RAS could also be active in neoplastic hematopoiesis. The aim of this study is to examine critical RAS elements in normal CD34+ hematopoietic stem cells and multiple myeloma (MM)-related progenitor cells. Materials and Methods: The study group comprised the total bone marrow cells (CBM) of 10 hematologically normal people, the CD34+ stem cell samples (CD34+CBM) of 9 healthy donors for allogeneic peripheral stem cell transplantation, and the CD34+ stem cell samples (CD34+MM) of 9 MM patients undergoing autologous peripheral stem cell transplantation. We searched for the gene expression of the major RAS components in healthy hematopoietic cells and myeloma cells by quantitative real-time polymerase chain reaction analysis. Results: RENIN, angiotensinogen (ANGTS), and angiotensin converting enzyme-I (ACE I) mRNA expression levels of CBM were significantly higher than those in myeloma patients (p=0.03, p=0.002, and p=0.0008, respectively). Moreover, RENIN and ANGTS mRNA expression levels were significantly higher in CD34+ stem cell samples of healthy allogeneic donors compared to those in myeloma patients (p=0.001 and p=0.01). However, ACE I expression levels were similar in CD34+CBM and CD34+MM hematopoietic cells (p=0.89). Conclusion: Although found to be lower than in the CBM and CD34+CBM hematopoietic cells, the local RAS components were also expressed in CD34+MM hematopoietic cells. This point should be kept in mind while focusing on the immunobiology of MM and the processing of autologous cells during the formation of transplantation treatment protocols.
    Turkish Journal of Haematology 06/2014; 31(2):136-42. DOI:10.4274/tjh.2013.0011 · 0.36 Impact Factor
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    • "Observations in KO mice provides evidence that points to a significant role for the RAS in the regulation of hematopoiesis and the development of hematopoietic progenitor cells (23–25). The central role of the RAS in regulating early hematopoiesis has been the focus of several reviews (23, 26–28). In addition to reduced/delayed hematopoiesis in ACE-KO mice, is the observation that expression of ACE demarcates early events in hematopoiesis both in the fetus and the adult. "
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    ABSTRACT: The renin-angiotensin system (RAS) has long been a known endocrine system that is involved in regulation of blood pressure and fluid balance. Over the last two decades, evidence has accrued that shows that there are local RAS that can affect cellular activity, tissue injury, and tissue regeneration. There are locally active ligand peptides, mediators, receptors, and signaling pathways of the RAS in the bone marrow (BM). This system is fundamentally involved and controls the essential steps of primitive and definitive blood-cell production. Hematopoiesis, erythropoiesis, myelopoiesis, thrombopoiesis, formation of monocytic and lymphocytic lineages, as well as stromal elements are regulated by the local BM RAS. The expression of a local BM RAS has been shown in very early, primitive embryonic hematopoiesis. Angiotensin-converting enzyme (ACE-1, CD143) is expressed on the surface of hemangioblasts and isolation of the CD143 positive cells allows for recovery of all hemangioblast activity, the first endothelial and hematopoietic cells, forming the marrow cavity in the embryo. CD143 expression also marks long-term blood-forming CD34+ BM cells. Expression of receptors of the RAS is modified in the BM with cellular maturation and by injury. Ligation of the receptors of the RAS has been shown to modify the status of the BM resulting in accelerated hematopoiesis after injury. The aim of the present review is to outline the known functions of the local BM RAS within the context of primitive and definitive hematopoiesis as well as modification of BM recovery by administration of exogenous ligands of the RAS. Targeting the actions of local RAS molecules could represent a valuable therapeutic option for the management of BM recovery after injury as well as neoplastic disorders.
    Frontiers in Endocrinology 10/2013; 4:157. DOI:10.3389/fendo.2013.00157
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    • "Apart from its well-studied roles in vasoconstriction, aldosterone release, and fluid balance, angiotensin II (AngII), the principal effector of the renin–angiotensin system (RAS), influences a selection of homeostatic and modulatory processes that can also serve as targets for dysregulation and subsequent development of pathological states. These include cellular growth (hypertrophy) and remodelling (fibrosis); dyslipidaemia; endothelial dysfunction, aneurysms and angiogenesis (Iwai and Horiuchi, 2009; Lu et al., 2008; Mehta and Griendling, 2007; Weiss et al., 2001); proinflammatory responses (Rompe et al., 2010; Schiffrin, 2010); stem cell programming and haematopoiesis (Heringer-Walther et al., 2009; Park and Zambidis, 2009; Zambidis et al., 2008); neuromodulation including cognition, memory and dementia (Li et al., 2010; Miners et al., 2009); and cancer, as reviewed by us (George et al., 2010). "
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    ABSTRACT: The angiotensin type 1 receptor (AT1R) transactivates the epidermal growth factor receptor (EGFR) to mediate cellular growth, although the molecular mechanisms are not resolved. To address this, we performed a functional siRNA of the human kinome in human mammary epithelial cells that demonstrate a robust AT1R-EGFR transactivation. We identified a suite of genes that both positively and negatively regulate AT1R-EGFR transactivation. Many candidates comprised components of EGFR signalling networks, whereas others, including TRIO, BMX and CHKA, had not been previously linked to EGFR transactivation. Individual knockdown of TRIO, BMX or CHKA attenuated tyrosine phosphorylation of the EGFR by angiotensin II stimulation, but not following direct stimulation of the EGFR with EGF, indicating that these genes function between the activated AT1R and the EGFR. Further investigation of TRIO and CHKA revealed that their activity is likely to be required for AT1R-EGFR transactivation. CHKA also mediated EGFR transactivation in response to another GPCR ligand, thrombin, indicating a pervasive role for CHKA in GPCR-EGFR crosstalk. Our study reveals the power of unbiased, functional genomic screens to identify new signalling mediators important for cell biology related to tissue remodelling in cardiovascular disease and cancer.
    Journal of Cell Science 09/2013; 126(23). DOI:10.1242/jcs.128280 · 5.43 Impact Factor
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