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 and Jingli Cao ()
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Yu Xia: Weill Cornell Medical College
Sierra Duca: Weill Cornell Medical College
Björn Perder: Weill Cornell Medical College
Friederike Dündar: Weill Cornell Medical College
Paul Zumbo: Weill Cornell Medical College
Miaoyan Qiu: Weill Cornell Medical College
Jun Yao: Weill Cornell Medical College
Yingxi Cao: Weill Cornell Medical College
Michael R. M. Harrison: Weill Cornell Medical College
Lior Zangi: Icahn School of Medicine at Mount Sinai
Doron Betel: Weill Cornell Medical College
Jingli Cao: Weill Cornell Medical College

Nature Communications, 2022, vol. 13, issue 1, 1-18

Abstract: 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 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.

Date: 2022
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DOI: 10.1038/s41467-022-35433-9

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