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

• Published in: Nature communications 2022-12, Vol.13 (1), p.7704-18, Article 7704
• Main Authors: Xia, Yu, Duca, Sierra, Perder, Björn, Dündar, Friederike, Zumbo, Paul, Qiu, Miaoyan, Yao, Jun, Cao, Yingxi, Harrison, Michael R. M., Zangi, Lior, Betel, Doron, Cao, Jingli
• Format: Article
• Language: English
• Subjects: 13/51; 14/19; 14/32; 38; 38/32; 45/41; 45/91; 631/136/142; 631/443/592/2725; 631/443/592/2726; 631/532/489; 64/116; Ablation; Animals; Cell differentiation; Cell number; Cells (biology); Danio rerio; Epicardium; Epithelial-Mesenchymal Transition - genetics; Extracellular Matrix Proteins - metabolism; Gene sequencing; Heart; Heart - physiology; Heart Injuries - genetics; Humanities and Social Sciences; Mesenchyme; multidisciplinary; Paracrine signalling; Pericardium; Progenitor cells; Proteoglycans - metabolism; Regeneration; Science; Science (multidisciplinary); Stem cells; Stem Cells - metabolism; Vertebrates; Zebrafish; Zebrafish - metabolism; Zebrafish Proteins - genetics; Zebrafish Proteins - metabolism
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-022-35433-9

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. The epicardium supports heart regeneration, though precisely how is unclear. Here the authors define an activated epicardial progenitor population as the source of essential cell types and paracrine factors for successful heart regeneration in zebrafish.