Developmental and Regenerative Biology of Multipotent Cardiovascular Progenitor Cells

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Circulation Research (Impact Factor: 11.02). 02/2011; 108(3):353-64. DOI: 10.1161/CIRCRESAHA.110.227066
Source: PubMed


Our limited ability to improve the survival of patients with heart failure is attributable, in part, to the inability of the mammalian heart to meaningfully regenerate itself. The recent identification of distinct families of multipotent cardiovascular progenitor cells from endogenous, as well as exogenous, sources, such as embryonic and induced pluripotent stem cells, has raised much hope that therapeutic manipulation of these cells may lead to regression of many forms of cardiovascular disease. Although the exact source and cell type remains to be clarified, our greater understanding of the scientific underpinning behind developmental cardiovascular progenitor cell biology has helped to clarify the origin and properties of diverse cells with putative cardiogenic potential. In this review, we highlight recent advances in the understanding of cardiovascular progenitor cell biology from embryogenesis to adulthood and their implications for therapeutic cardiac regeneration. We believe that a detailed understanding of cardiogenesis will inform future applications of cardiovascular progenitor cells in heart failure therapy and regenerative medicine.

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    • "Since the genuine nature of Sca-1 cells has been a matter of debate and a fibroblast-like character of the cells have been suggested (Barile et al., 2007; Sturzu and Wu, 2011) we comparatively profiled the gene expression of Sca-1þ cells and Sca-1-cells using microarrays. The analysis of the expression data revealed that Sca-1þ cells express higher levels of progenitor cell markers than Sca-1-cells. "
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    ABSTRACT: Stem cell therapy is a promising new option for patients suffering from heart failure. Though many clinical studies show encouraging results, little is known about the signals which cause stem cells to home to diseased but not to healthy hearts. We hypothesized that aldosterone as one of the main players of heart failure functions as an attractant for progenitor cells and stimulates their migration. Stem cell antigen-1 (Sca-1) positive cells were isolated from the hearts of wild type FVB mice via magnetic cell sorting. The migration rate of the cells was determined using aldosterone as an attractant in a modified Boyden chamber (n = 5). Aldosterone led to a dose dependent increase in migration rate and this effect could be prevented by adding its blocker eplerenone. The mineralocorticoid receptor could be detected on Sca-1+ cells via western blot and immunofluorescence. Therefore, aldosterone seems to play a role in stem cell migration and there the effect is most likely mediated by the mineralocorticoid receptor. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    Journal of Cellular Physiology 04/2015; 230(11). DOI:10.1002/jcp.25013 · 3.84 Impact Factor
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    • "Nevertheless, given that mouse models are inadequate for establishing human protein expression profiles, as demonstrated for c-KIT here and previously for SIRPA (Dubois et al., 2011), obtaining experimental data from early human embryos is a future priority. Molecular markers permitting the identification and isolation of distinct cardiogenic cell populations will be useful for understanding the developmental logic of human cardiogenesis, pharmaceutical screening and regenerative medicine (Burridge et al., 2012; Sturzu and Wu, 2011; Thavandiran et al., 2013; Tiscornia et al., 2011). In this context, the temporal and contingent relationships of the cell lineage markers described here form a foundation for placing newly identified markers within the cardiovascular lineage fate map. "
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    ABSTRACT: The study of human cardiogenesis would benefit from a detailed cell lineage fate map akin to that established for the hematopoietic lineages. Here we sought to define cell lineage relationships based on expression of NKX2-5 and the cell surface markers VCAM1, SIRPA and CD34 during human cardiovascular development. Expression of NKX2-5GFP was used to identify cardiac progenitors and cardiomyocytes generated during the differentiation of NKX2-5GFP/w human embryonic stem cells (hESCs). Cardiovascular cell lineages sub-fractionated on the basis of SIRPA, VCAM1 and CD34 expression were assayed for differentiation potential and gene expression. The NKX2-5posCD34pos population gave rise to endothelial cells that rapidly lost NKX2-5 expression in culture. Conversely, NKX2-5 expression was maintained in myocardial committed cells, which progressed from being NKX2-5posSIRPApos to NKX2-5posSIRPAposVCAM1pos. Up-regulation of VCAM1 was accompanied by expression of myofilament markers and reduced clonal capacity, implying a restriction of cell fate potential. Combinatorial expression of NKX2-5, SIRPA, VCAM1 and CD34 can be used to define discrete stages of cardiovascular cell lineage differentiation. These markers identify specific stages of cardiomyocyte and endothelial lineage commitment and, thus provide a scaffold for establishing a fate map of early human cardiogenesis.
    Stem Cell Research 07/2014; 13(1). DOI:10.1016/j.scr.2014.04.016 · 3.69 Impact Factor
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    • "Stem cell-based therapies offer an alternative therapeutic solution to treat a number of ischemic heart diseases. Accumulating evidence demonstrated experimentally that various cell types have regenerative potential: skeletal myoblasts (Murry et al., 1996; Taylor et al., 1998), fi broblasts (Galli et al., 2005), SMCs (Li et al., 1999), fetal myocytes (Soonpaa et al., 1994; Koh et al., 1995), embryonic stem cells (ESCs) (Cao et al., 2006), bone marrow-derived cells (BMCs) (Orlic et al., 2001; Kawamoto et al., 2003; Urbich et al., 2005; Iwasaki et al., 2006; Kawamoto et al., 2006), induced pluripotent stem cells (iPSCs) (Sturzu and Wu, 2011), and cardiac stem/progenitor cells (CSCs or CPCs) (Bearzi et al., 2007). Very recently, the isolation and ex vivo expansion of CPCs from ischemic hearts provide new therapeutic strategies for myocardial regeneration and repair. "
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    ABSTRACT: Recent accumulating studies have reported that hypoxic preconditioning during ex vivo expansion enhanced the self-renewal or differentiation of various stem cells and provide an important strategy for the adequate modulation of oxygen in culture conditions, which might increase the functional bioactivity of these cells for cardiac regeneration. In this study, we proposed a novel priming protocol to increase the functional bioactivity of cardiac progenitor cells (CPCs) for the treatment of cardiac regeneration. Firstly, patient-derived c-kit(+) CPCs isolated from the atrium of human hearts by enzymatic digestion and secondly, pivotal target molecules identifi ed their differentiation into specific cell lineages. We observed that hCPCs, in response to hypoxia, strongly activated ERK phosphorylation in ex vivo culture conditioning. Interestingly, pre-treatment with an ERK inhibitor, U0126, significantly enhanced cellular proliferation and tubular formation capacities of CPCs. Furthermore, we observed that hCPCs efficiently maintained the expression of the c-kit, a typical stem cell marker of CPCs, under both hypoxic conditioning and ERK inhibition. We also show that hCPCs, after preconditioning of both hypoxic and ERK inhibition, are capable of differentiating into smooth muscle cells (SMCs) and cardiomyocytes (CMs), but not endothelial cells (ECs), as demonstrated by the strong expression of α-SMA, Nkx2.5, and cTnT, respectively. From our results, we conclude that the functional bioactivity of patient-derived hCPCs and their ability to differentiate into SMCs and CMs can be effi ciently increased under specifically defined culture conditions such as shortterm hypoxic preconditioning and ERK inhibition.
    Biomolecules and Therapeutics 05/2013; 21(3):196-203. DOI:10.4062/biomolther.2013.019 · 1.73 Impact Factor
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