| Summary: | <p>Following cardiac injury, adult mammals are unable to regenerate their hearts. In contrast, zebrafish maintain the ability to regenerate their hearts throughout adulthood. This is mainly driven by the dedifferentiation and proliferation of existing cardiomyocytes. However, the mechanisms underlying cardiomyocyte dedifferentiation remain unknown, while additional non-cardiomyocyte contributions to newly formed myocardium post-injury have not been unequivocally excluded.</p>
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<p>The epicardium is a single layer of multipotent progenitor cells that covers the outer surface of the heart. In embryonic development, it supports myocardial growth and transdifferentiates to produce a number of cardiac cell types such as perivascular cells. Whether the epicardium is a progenitor source of cardiomyocytes remains a controversial question. In adulthood, the epicardium is quiescent, however, it becomes ‘reactivated’ following injury, re-expressing embryonic epicardial genes including <i>wt1b</i>.</p>
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<p>I established and validated a number of transgenic zebrafish lines expressing, namely, cell-specific inducible Cre recombinases, a system for Cre-based nuclei labelling, isolation and sequencing, and cell-specific inducible Cas9 endonucleases. These tools facilitated the examination of the relative contributions of <i>wt1b</i><sup>+</sup> cells to the developing and regenerating myocardium. Moreover, they will help to identify the molecular pathways in which <i>wt1b</i> acts to regulate cardiomyocyte production across multiple time points.</p>
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<p>I discovered that the <i>wt1b</i>-expressing epicardium is a progenitor source of cardiomyocytes during zebrafish cardiac development and identified a significant contribution of the <i>wt1b</i> cell lineage to myocardial regeneration after cardiac injury. My future work will aim to determine whether there is a cell autonomous <i>wt1b</i><sup>+</sup> epicardial contribution to the regenerating myocardium and/or whether activation of <i>wt1b</i> in existing cardiomyocytes is required for dedifferentiation prior to cell cycle re-entry and proliferation.</p>
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<p>This thesis demonstrates that Wt1b plays a significant and previously underappreciated role in the ontogenesis and repair of the zebrafish myocardium. Understanding the mechanisms by which the zebrafish heart can regenerate may elucidate potential therapeutic targets for human heart attack patients.</p>
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