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Proc Natl Acad Sci U S A. 2018 Dec 26;115(52):E12245-E12254. doi: 10.1073/pnas.1805829115. Epub 2018 Dec 7.

Profiling proliferative cells and their progeny in damaged murine hearts.

Author information

1
Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences and University Medical Centre Utrecht, 3584 CT Utrecht, The Netherlands.
2
Oncode Institute, Hubrecht Institute, 3584 CT Utrecht, The Netherlands.
3
Department of Biology, École Normale Supérieure de Lyon, 69007 Lyon, France.
4
Department of Medical Physiology, Academic Medical Center, Amsterdam University Medical Centers, 1105 AZ Amsterdam, The Netherlands.
5
Princess Máxima Center for Pediatric Oncology, 3584 CT Utrecht, The Netherlands.
6
Department of Translational Neuroscience, Brain Center Rudolf Magnus, University Medical Center Utrecht and Utrecht University, 3584 CG Utrecht, The Netherlands.
7
The Francis Crick Institute, London NW1 1AT, United Kingdom.
8
Molecular Cardiology, University Medical Center Utrecht, 3584 CG Utrecht, The Netherlands.
9
Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences and University Medical Centre Utrecht, 3584 CT Utrecht, The Netherlands; h.clevers@hubrecht.eu.

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.

KEYWORDS:

cardiac regeneration; fibroblasts; lineage tracing; single-cell transcriptomics; stem cells

PMID:
30530645
PMCID:
PMC6310797
DOI:
10.1073/pnas.1805829115
[Indexed for MEDLINE]
Free PMC Article

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