Activation of a transient progenitor state in the epicardium is required for zebrafish heart regeneration

Yu Xia, Sierra Duca, Björn Perder, Friederike Dündar, Paul Zumbo, Miaoyan Qiu, Jun Yao, Yingxi Cao, Michael R.M. Harrison, Lior Zangi, Doron Betel, Jingli Cao

Research output: Contribution to journalArticlepeer-review

11 Scopus citations


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 define the epithelial and mesenchymal subsets of the epicardium. We further identify a transiently activated epicardial progenitor cell (aEPC) subpopulation marked by ptx3a and col12a1b expression. Upon cardiac injury, aEPCs emerge from the epithelial epicardium, migrate to enclose the wound, undergo epithelial-mesenchymal transition (EMT), and differentiate into mural cells and pdgfra+hapln1a+ mesenchymal epicardial cells. These EMT and differentiation processes are regulated by the Tgfβ pathway. Conditional ablation of aEPCs blocks 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.

Original languageEnglish
Article number7704
JournalNature Communications
Issue number1
StatePublished - Dec 2022


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