Profiling proliferative cells and their progeny in damaged murine hearts

TY - JOUR

T1 - Profiling proliferative cells and their progeny in damaged murine hearts

AU - Kretzschmar, Kai

AU - Post, Yorick

AU - Bannier-Hélaouët, Marie

AU - Mattiotti, Andrea

AU - Drost, Jarno

AU - Basak, Onur

AU - Li, Vivian S W

AU - van den Born, Maaike

AU - Gunst, Quinn D

AU - Versteeg, Danielle

AU - Kooijman, Lieneke

AU - van der Elst, Stefan

AU - van Es, Johan H

AU - van Rooij, Eva

AU - van den Hoff, Maurice J B

AU - Clevers, Hans

N1 - Copyright © 2018 the Author(s). Published by PNAS.

PY - 2018/12/26

Y1 - 2018/12/26

N2 - The significance of cardiac stem cell (CSC) populations for cardiac regeneration remains disputed. Here, we apply the most direct definition of stem cell function (the ability to replace lost tissue through cell division) to interrogate the existence of CSCs. By single-cell mRNA sequencing and genetic lineage tracing using two Ki67 knockin mouse models, we map all proliferating cells and their progeny in homoeostatic and regenerating murine hearts. Cycling cardiomyocytes were only robustly observed in the early postnatal growth phase, while cycling cells in homoeostatic and damaged adult myocardium represented various noncardiomyocyte cell types. Proliferative postdamage fibroblasts expressing follistatin-like protein 1 (FSTL1) closely resemble neonatal cardiac fibroblasts and form the fibrotic scar. Genetic deletion of Fstl1 in cardiac fibroblasts results in postdamage cardiac rupture. We find no evidence for the existence of a quiescent CSC population, for transdifferentiation of other cell types toward cardiomyocytes, or for proliferation of significant numbers of cardiomyocytes in response to cardiac injury.

AB - The significance of cardiac stem cell (CSC) populations for cardiac regeneration remains disputed. Here, we apply the most direct definition of stem cell function (the ability to replace lost tissue through cell division) to interrogate the existence of CSCs. By single-cell mRNA sequencing and genetic lineage tracing using two Ki67 knockin mouse models, we map all proliferating cells and their progeny in homoeostatic and regenerating murine hearts. Cycling cardiomyocytes were only robustly observed in the early postnatal growth phase, while cycling cells in homoeostatic and damaged adult myocardium represented various noncardiomyocyte cell types. Proliferative postdamage fibroblasts expressing follistatin-like protein 1 (FSTL1) closely resemble neonatal cardiac fibroblasts and form the fibrotic scar. Genetic deletion of Fstl1 in cardiac fibroblasts results in postdamage cardiac rupture. We find no evidence for the existence of a quiescent CSC population, for transdifferentiation of other cell types toward cardiomyocytes, or for proliferation of significant numbers of cardiomyocytes in response to cardiac injury.

U2 - 10.1073/pnas.1805829115

DO - 10.1073/pnas.1805829115

M3 - Article

C2 - 30530645

SN - 0027-8424

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

ER -