A Transient Epicardial Progenitor Population Orchestrates Zebrafish Heart Regeneration

The epicardium is a mesothelial tissue surrounding the vertebrate heart. In zebrafish, it is a source of progenitors for different cell types (including smooth muscle cells, pericytes, and fibroblasts) that are essential for development and regeneration. Epicardial cells are also responsible for paracrine signaling and extracellular matrix constituents involved in cardiomyocyte expansion and angiogenesis following cardiac injury in zebrafish. Their importance for mammalian heart repair has also been reported. Nevertheless, molecular characterization of this adult epicardial “progenitor state” has remained elusive.

Recently, Xia et al. used single-cell RNA sequencing (scRNA-seq) to study epicardial cells from uninjured and regenerating adult zebrafish hearts and identified a transiently activated ptx3a-/col12a1b-positive epicardial progenitor cell (aEPC) subpopulation (1). The authors found that these cells migrate to a cardiac lesion, undergo epithelial-mesenchymal transition (EMT), and differentiate into mural cells and pdgfra-/hapln1a-positive mesenchymal epicardial cells in a process mediated by Tgfβ pathway signaling. Comparison of the zebrafish data with an adult mouse epicardial cell scRNA-seq dataset revealed many important similarities, and some distinctions, in expression profiles. Together, the findings of Xia et al. make a compelling case for adult epicardial cell plasticity and the vital role of aEPCs in cardiac regeneration, with potential application to mammalian heart repair.

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