Profiling proliferative cells and their progeny in damaged murine hearts

Author:

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

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.

Funder

Hartstichting

Human Frontier Science Program

ZonMw

Publisher

Proceedings of the National Academy of Sciences

Subject

Multidisciplinary

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