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  • Both CAR and DAF have been

    2018-11-12

    Both CAR and DAF have been implicated in CVB infection. Molecular events underlying CVB entry have been described for polarized (Coyne and Bergelson, 2006) and nonpolarized monensin cost (Patel et al., 2009). However, the exact mechanism involved in CVB infection of cardiomyocytes is unknown. Moreover, some aspects of infection could be specific to human cells. For example, CVB can interacts with human and murine CAR. However, unlike human DAF, CVB does not bind to rodent DAF protein analogues (Spiller et al., 2000) precluding use of a suitable rodent model. Additionally, design of a human in vitro model system has been hindered by difficulties associated with culturing human cardiomyocytes derived from adult heart tissues as well as by low availability of cardiac cell cultures from fetal sources (Kandolf et al., 1985). The emergence of embryonic stem cells and protocols for cardiomyocyte differentiation has allowed modern research to overcome these problems. After testing our cell lines for the presence of viral receptors, we subsequently assessed the susceptibility of these cell lines to CVB infection. Pioneer work by Feuer et al. performed in mice revealed CVB3 preferentially targets proliferating neural stem cells located in the neonatal central nervous system (Feuer et al., 2003, 2005). In our study, we extended these observations showing both hESCs and hESC-EB presented susceptibility to CVB infection. Several lines of evidence suggest host cell status may play a key role in determining CVB infection outcome. In this regard, proliferation appears to favour productive CVB infection (Tabor-Godwin et al., 2010), and perhaps also contribute to CVB enhanced replication observed in hESC compared to hESC-EB. The data presented herein agree with previous studies performed with cardiomyocytes derived from human fetal tissue (Kandolf et al., 1985) or newborn mice (Gomez et al., 1993). We also show that IFN-Iβ administration prior to infection was able to reduce viral replication and subsequent cell death. This cytokine was chosen because previous published reports have shown IFN-Iβ treatment eliminates cardiotropic viruses, improving left ventricular function in patients with myocardial persistence of viral genomes and left ventricular dysfunction (Kuhl et al., 2003). Although clinical trials with IFN are still in progress, the results seem promising (Matsumori, 2007). The model described here is novel, relatively simple and can be easily reproduced in monensin cost any laboratory currently working on hESC. Our findings suggest this model can be useful for the evaluation of potential drug therapies for viral myocarditis.
    Conclusions
    Materials and Methods
    Disclosures
    Acknowledgments
    Introduction Embryonic stem cells (ESCs) are undifferentiated cells that can differentiate into all adult cell types. Following the initial isolation of mouse ESCs (mESCs) in 1981 (Evans and Kaufman, 1981), methods for the in vitro differentiation of mESC-derived cardiomyocytes (mESC-CMs) have been well established. The most common protocol involves the cultivation of three-dimensional aggregates called embryoid bodies (EBs) which, when plated, give rise to spontaneously beating cardiomyocytes within a mixed cell aggregate (Wobus et al., 2002). Expression profiling of the transcription factors involved with heart development in vivo, as well as electrophysiological and morphological studies, has shown that ESC-CMs exhibit properties indicative of early myocardial development (Boheler et al., 2002; Fijnvandraat et al., 2003). Nevertheless, some studies have reported the successful engraftment of these developing ESC-CMs to injured myocardium (Laflamme et al., 2007; Klug et al., 1996; Hodgson et al., 2004). In addition, these ESC-CMs can potentially serve as readily available and functional in vitro cardiac models for basic research and in drug discovery and development programs (Pouton and Haynes, 2007). Consideration for the use of ESC-CMs in replacement therapies and as models of cardiac activity must be linked to a comprehensive characterization of their basic physiological and pharmacological properties, an area not well established.