Natural and Synthetic Regulators of Embryonic Stem Cell Cardiogenesis

Burnham Institute for Medical Research, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.
Pediatric Cardiology (Impact Factor: 1.31). 04/2009; 30(5):635-42. DOI: 10.1007/s00246-009-9409-2
Source: PubMed


Debilitating cardiomyocyte loss underlies the progression to heart failure. Although there have been significant advances in treatment, current therapies are intended to improve or preserve heart function rather than regenerate lost myocardium. A major hurdle in implementing a cell-based regenerative therapy is the inefficient differentiation of cardiomyocytes from either endogenous or exogenous stem cell sources. Moreover, cardiomyocytes that develop in human embryonic stem cell (hESC) or human-induced pluripotent stem cell (hIPSC) cultures are comparatively immature, even after prolonged culture, and differences in their calcium handling, ion channel, and force generation properties relative to adult cardiomyocytes raise concerns of improper integration and function after transplantation. Thus, the discovery of natural and novel small molecule synthetic regulators of differentiation and maturation would accelerate the development of stem-cell-based myocardial therapies. Here, we document recent advances in defining natural signaling pathways that direct the multistep cardiomyogenic differentiation program and the development of small molecules that might be used to enhance differentiation as well as the potential characteristics of lead candidates for pharmaceutical stimulation of endogenous myocardial replacement.

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Available from: Erik Willems, Oct 08, 2015
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    • "The EB methodology can also be adapted to high-throughput using flasks with rotating paddles (Amit et al., 2011), or by using a simple suspension culture to produce hiPSC-derived cardiomyocytes in commercial quantities (Ma et al., 2011). The elimination of growth factors from the monolayer protocol (Lian et al., 2011) permits a substantial reduction in costs, and along with the application of other low molecular weight compounds (Willems et al., 2009), will continue to improve scalability. "
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    ABSTRACT: Cardiovascular disease is a leading cause of death worldwide. The limited capability of heart tissue to regenerate has prompted methodological developments for creating de novo cardiomyocytes, both in vitro and in vivo. Beyond uses in cell replacement therapy, patient-specific cardiomyocytes may find applications in drug testing, drug discovery, and disease modeling. Recently, approaches for generating cardiomyocytes have expanded to encompass three major sources of starting cells: human pluripotent stem cells (hPSCs), adult heart-derived cardiac progenitor cells (CPCs), and reprogrammed fibroblasts. We discuss state-of-the-art methods for generating de novo cardiomyocytes from hPSCs and reprogrammed fibroblasts, highlighting potential applications and future challenges.
    Cell stem cell 01/2012; 10(1):16-28. DOI:10.1016/j.stem.2011.12.013 · 22.27 Impact Factor
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    • "As a consequence, high-throughput molecular screening technology has been exploited to search for compounds with the potential to induce cardiomyogenesis in vitro. To date, a few studies have published results from such screening approaches, describing the identification of novel small molecules that appear to stimulate the generation of cardiomyocytes from pluripotent stem cells, including cardiogenols, ascorbic acid, isoxazolylserines , sulfonyl hydrazones, and DMSO [69]. All of these molecules were identified based on their ability to upregulate late-stage markers of cardiogenesis. "
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    ABSTRACT: The ability of human pluripotent stem cells to differentiate towards the cardiac lineage has attracted significant interest, initially with a strong focus on regenerative medicine. The ultimate goal to repair the heart by cardiomyocyte replacement has, however, proven challenging. Human cardiac differentiation has been difficult to control, but methods are improving, and the process, to a certain extent, can be manipulated and directed. The stem cell-derived cardiomyocytes described to date exhibit rather immature functional and structural characteristics compared to adult cardiomyocytes. Thus, a future challenge will be to develop strategies to reach a higher degree of cardiomyocyte maturation in vitro , to isolate cardiomyocytes from the heterogeneous pool of differentiating cells, as well as to guide the differentiation into the desired subtype, that is, ventricular, atrial, and pacemaker cells. In this paper, we will discuss the strategies for the generation of cardiomyocytes from pluripotent stem cells and their characteristics, as well as highlight some applications for the cells.
    04/2011; 2011(21):383709. DOI:10.4061/2011/383709
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    ABSTRACT: Cardiomyocytes exhibit robust proliferative activity during development. After birth, cardiomyocyte proliferation is markedly reduced. Consequently, regenerative growth in the postnatal heart via cardiomyocyte proliferation (including, by inference, via proliferation of stem cell-derived cardiomyocytes) is limited and often insufficient to effect repair following injury. Here we review methodologies which employ the mouse as a model system to study cardiac regeneration, and in particular cardiomyocyte replenishment, in health and disease.
    Drug Discovery Today Disease Models 09/2008; 5(3):165-171. DOI:10.1016/j.ddmod.2009.03.002
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