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Profiling proliferative cells and their progeny in damaged murine hearts

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journal contribution
posted on 20.08.2020, 16:48 by Kai Kretzschmar, Yorick Post, Marie Bannier-Hélaouët, Andrea Mattiotti, Jarno Drost, Onur Basak, Vivian SW Li, Maaike van den Born, Quinn D Gunst, Danielle Versteeg, Lieneke Kooijman, Stefan van der Elst, Johan H van Es, Eva van Rooij, Maurice JB van den Hoff, Hans Clevers
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.