TY - JOUR
T1 - Activation of a transient progenitor state in the epicardium is required for zebrafish heart regeneration
AU - Xia, Yu
AU - Duca, Sierra
AU - Perder, Björn
AU - Dündar, Friederike
AU - Zumbo, Paul
AU - Qiu, Miaoyan
AU - Yao, Jun
AU - Cao, Yingxi
AU - Harrison, Michael R.M.
AU - Zangi, Lior
AU - Betel, Doron
AU - Cao, Jingli
N1 - Funding Information:
We thank Adedeji A. Afolalu, Chaim Shapiro, Soji Hosten, and Chelsea Quaies for fish care, Naoki Mochizuki for the Tg(pdgfrb:EGFP) line, and Geoffrey Pitt, Junsu Kang, and Todd Evans for comments on the manuscript. This work was supported by Rudin Foundation fellowships to Y.X. and J.Y., a predoctoral training grant position (T32-HD060600) and a predoctoral fellowship (F31-HL158168) from National Institutes of Health (NIH) to S.D., a predoctoral training grant position in Stem Cell Biology and Regenerative Medicine from New York State Stem Cell Science program (NYSTEM) to B.P., American Heart Association (AHA) Career Development Award (AHA941434) to M.R.M.H., NIH grants (R01HL142768 and R01HL149137) to L.Z., AHA Career Development Award (18CDA34110108), Weill Cornell Start-up fund, and NIH grant (R01HL155607) to J.C. ncv22
Funding Information:
We thank Adedeji A. Afolalu, Chaim Shapiro, Soji Hosten, and Chelsea Quaies for fish care, Naoki Mochizuki for the Tg(pdgfrb:EGFP)ncv22line, and Geoffrey Pitt, Junsu Kang, and Todd Evans for comments on the manuscript. This work was supported by Rudin Foundation fellowships to Y.X. and J.Y., a predoctoral training grant position (T32-HD060600) and a predoctoral fellowship (F31-HL158168) from National Institutes of Health (NIH) to S.D., a predoctoral training grant position in Stem Cell Biology and Regenerative Medicine from New York State Stem Cell Science program (NYSTEM) to B.P., American Heart Association (AHA) Career Development Award (AHA941434) to M.R.M.H., NIH grants (R01HL142768 and R01HL149137) to L.Z., AHA Career Development Award (18CDA34110108), Weill Cornell Start-up fund, and NIH grant (R01HL155607) to J.C.
Publisher Copyright:
© 2022, The Author(s).
PY - 2022/12
Y1 - 2022/12
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85144122934&partnerID=8YFLogxK
U2 - 10.1038/s41467-022-35433-9
DO - 10.1038/s41467-022-35433-9
M3 - Article
C2 - 36513650
AN - SCOPUS:85144122934
SN - 2041-1723
VL - 13
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 7704
ER -