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    • Additionally it would be highly

    2018-11-12

    Additionally, it would be highly desirable to manipulate CSCs to improve their survival and direct them efficiently to the myocyte lineage. A recently developed technology to deliver mRNA in vivo shows promise. Modified RNA (modRNA) encoding human vascular endothelial growth factor-A (VEGF-A) improves heart function and enhances the long-term survival of the murine recipients. These improvements were at least partly mediated by an expansion of epicardial Wt1-positive CSCs and their promotion toward the endothelial and cardiomyocyte lineage (Zangi et al., 2013). Most studies on adult heart regeneration have been conducted in rodents with hearts that are several hundred-fold smaller than the human equivalents. Furthermore, the expression profile of CSCs might be different in rodents compared with humans. Sca1, for example, is not conserved throughout species and does not exist in humans. The .therapeutic efficiency of CSCs, stem cell-derived cardiomyocytes or small molecules delivered to the myocardium can only be assessed in a clinical-relevant model of cardiac disease. Animal models that better resemble the human situation are therefore greatly needed to translate the knowledge we have obtained in lower vertebrates and rodents to the clinic. Accordingly, in a recent study conducted in non-human primates, Chong and colleagues showed that a graft of human embryonic stem cell-derived cardiomyocytes remuscularized the infarcted macaque heart and electrically coupled to the host myocardium (Chong et al., 2014). Today, site-specific nucleases such as TALEN and CRISPR/Cas make it possible to introduce custom modifications into genomic DNA (genome editing) [for review see (Gaj et al., 2013)]. This technology allows, for the first time, the generation of transgenic animals without having to establish stable ES cell lines. Recently, a Cre-inducible EGFP reporter pig line was generated using TALEN-mediated genomic editing of the ROSA26 locus (Li et al., 2014). Swine has traditionally served as a model animal for cardiac surgeons because their heart physiology closely resembles the human. Therefore, genome editing technology has the potential to facilitate translational studies to delineate the regulation of myocardial regeneration and thereby facilitate the stimulation of “regenerative” pathways to treat cardiac diseases.
    Introduction In purchase PHA-793887 to adult mammals, amphibians, reptiles, and zebrafish regenerate cardiomyocytes after myocardial injury (Jopling et al., 2010; Oberpriller and Oberpriller, 1974). The research community has directed attention to two principal strategies to regenerate myocardium: Use of stem and progenitor cells to repair damaged myocardium and enhancement of endogenous regenerative mechanisms (Garbern and Lee, 2013). This review focuses on endogenous regeneration mechanisms by cardiomyocyte proliferation.
    Historical and current perspectives in cardiac regeneration Anecdotal reports over the past 100years have shown mitoses of cardiomyocyte nuclei; however, evidence for cardiomyocyte division remained elusive. The first systematic and quantitative examinations of the cellular mechanisms of human heart growth were published in the 1950s (Linzbach, 1950; Linzbach, 1960). One study examined the increase of cardiomyocyte cross-sectional area in the left ventricular papillary muscle in humans and concluded that cardiomyocyte enlargement could fully account for physiologic myocardial growth between birth and adulthood (Linzbach, 1950, 1960). Because examining orthogonally sectioned papillary muscles is associated with biases, the validity of extrapolating these results to the entire heart is limited. Still, historically, the mammalian heart has been viewed as a post-mitotic organ in which the primary parenchymal cells, cardiomyocytes, do not increase in number after birth (Zak, 1973; Linzbach, 1950). Additional classical studies of cardiomyocyte proliferation used microscopy to visualize mitotic figures. However, these approaches probably did not have the precision necessary for definitive visualization of cardiomyocyte cytokinesis nor the throughput for quantifying rare events. Although not conclusive, these studies led to two paradigms: First, unlike skeletal muscle, the adult heart does not have progenitors supporting the generation of new cardiomyocytes. The second paradigm argued that there is a single cellular mechanism of post-natal developmental and pathological heart growth: cardiomyocyte enlargement (Rumyantsev and Carlson, 1991; Borisov and Claycomb, 1995). In the latter-20th century, technical advances, including use of confocal microscopy to visualize cell cycle events, automated analyses of large cell populations, and genetic and metabolic labeling for cellular fate mapping, have provided new data. This has advanced a new cellular paradigm, which includes adult cardiomyocyte renewal, while incorporating the significant role that cardiomyocyte enlargement plays in physiologic and pathologic heart growth.