The adult mammalian heart lacks any appreciable capacity to regenerate ischemia-damaged muscle. By comparison, injured zebrafish hearts mount an impressive regenerative response driven by robust myocardial proliferation. My laboratory’s research program is driven by the simple assumption that a complete understanding of cardiomyocyte proliferation regulatory mechanisms in zebrafish could be leveraged to promote heart regeneration in humans. Here, I will discuss recent advances in our understanding of zebrafish heart regeneration by focusing on our efforts to characterize the influences of epigenetic mechanisms, the Notch signaling pathway, and myocardial ploidy on regulating cardiomyocyte proliferation. In addition, I will discuss how the zebrafish might be utilized to identify pharmacological drivers of myocardial proliferation that could be employed for clinical benefit.

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