Developmental and Regenerative Biology of Multipotent Cardiovascular Progenitor Cells

CPZN 3224 Simches Building, Massachusetts General Hospital, 185 Cambridge St, Boston, MA 02114, USA.
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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    • "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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    • "The origin of the CSC population remains unclear. They are either believed to be the progeny of mesenchymal cells from the bone marrow, which homed to the heart through systemic circulation, or to correspond to cellular remnants of the embryonic heart [3]. During embryogenesis, a tightly orchestrated gene expression program involving cardiac specific genes and transcription factors that are activated in succession is initiated, coordinating heart development, along with the differentiation of the main cardiac cell lineages [4]. "
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    ABSTRACT: The identification of cardiac cells with stem cell properties changed the paradigm of the heart as a post mitotic organ. These cells proliferate and differentiate into cardiomyocytes, endothelial and vascular smooth muscle cells, providing for cardiac cell homeostasis and regeneration. microRNAs are master switches controlling proliferation and differentiation, in particular regulating stem cell biology and cardiac development. Modulation of microRNAs -regulated gene expression networks holds the potential to control cell fate and proliferation, with predictable biotechnologic and therapeutic applications. To obtain insights into the regulatory networks active in cardiac stem cells, we characterized the expression profile of 95 microRNAs with reported functions in stem cell and tissue differentiation in mouse cardiac stem cells, and compared it to that of mouse embryonic heart and mesenchymal stem cells. The most highly expressed microRNAs identified in cardiac stem cells are known to target key genes involved in the control of cell proliferation and adhesion, vascular function and cardiomyocyte differentiation. We report a subset of differentially expressed microRNAs that are proposed to act as regulators of differentiation and proliferation of adult cardiac stem cells, providing novel insights into active gene expression networks regulating their biological properties.
    PLoS ONE 05/2013; 8(5):e63041. DOI:10.1371/journal.pone.0063041 · 3.23 Impact Factor
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