Activation of an injury-associated transient progenitor state in the epicardium is required for zebrafish heart regeneration

Abstract

The epicardium, a mesothelial cell tissue that encompasses vertebrate hearts, supports heart regeneration after injury through paracrine effects and as a source of multipotent progenitors. However, the progenitor state in the adult epicardium has yet to be defined. Through single-cell RNA-sequencing of isolated epicardial cells from uninjured and regenerating adult zebrafish hearts, we defined the epithelial and mesenchymal subsets of the epicardium. We further identified a transiently activated epicardial progenitor cell (aEPC) subpopulation marked byptx3aandcol12a1bexpression. Upon cardiac injury, aEPCs emerge from the epithelial epicardium, migrate to enclose the wound, undergo epithelial-mesenchymal transition (EMT), and differentiate into mural cells andpdgfra+hapln1a+mesenchymal epicardial cells. These EMT and differentiation processes are regulated by the Tgfβ pathway. Conditional ablation of aEPCs blocked heart regeneration through reduced Nrg1 expression and mesenchymal cell number. Our findings identify a transient progenitor population of the adult epicardium that is indispensable for heart regeneration and highlight it as a potential target for enhancing cardiac repair.