Profiling proliferative cells and their progeny in damaged murine hearts

Kai Kretzschmar, Yorick Post, Marie Bannier-Hélaouët, Andrea Mattiotti, Jarno Drost, Onur Basak, Vivian S W Li, Maaike van den Born, Quinn D Gunst, Danielle Versteeg, Lieneke Kooijman, Stefan van der Elst, Johan H van Es, Eva van Rooij, Maurice J B van den Hoff, Hans Clevers

Research output: Contribution to journal/periodicalArticleScientificpeer-review

Abstract

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.

Original languageEnglish
JournalProceedings of the National Academy of Sciences of the United States of America
Early online date07 Dec 2018
DOIs
Publication statusPublished - 26 Dec 2018

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