Dissecting epicardial contributions to zebrafish heart regeneration at the single-cell level

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Abstract After an injury, such as myocardial infarction (MI), the adult human heart possesses only minimal regenerative capabilities. In contrast to humans and most mammals, the adult zebrafish possesses a remarkable ability to resolve fibrotic scarring and regenerate cardiac muscle after injury. Since there are currently no clinical regenerative therapies for MI-induced injuries, there persists a great need in the biomedical research community to understand the pro-regenerative machinery that enable robust zebrafish heart regeneration. Indispensable to this regenerative process is the epicardium, which is the outermost tissue layer of the heart. By contributing key paracrine signals and pro-regenerative cell types, the epicardium promotes cardiomyocyte (CM) proliferation and revascularization of the injury site. That being said, the precise mechanisms of these molecular and cellular processes are largely unknown, thus raising many questions in regard to the regulation of zebrafish heart regeneration. To address these questions, we performed single-cell RNA sequencing of isolated epicardial cells from injured and uninjured adult zebrafish hearts. Preliminary analysis identified an adult epicardial progenitor cell subpopulation that has the potential to differentiate into perivascular cells to facilitate angiogenesis. Here, through genetic ablation and lineage tracing, we aim to determine the cellular and molecular contributions of these progenitors to heart regeneration. Further analysis suggests that the Tgfb pathway regulates the proliferation and differentiation of these epicardial progenitors. To gain a greater understanding of the underlying regulatory mechanisms, we will further define the regenerative role of the Tgfb pathway in the epicardium using genetic gain/loss-of function assays and modified RNA injections. In sum, this project may ultimately inform strategies to target the pro-regenerative potential of epicardial progenitors to improve heart repair and function in MI patients.