SignificanceThe adult mammalian heart does not functionally repair itself after injury. Therefore, identification of cardiac stem cell (CSC) populations is of great interest for regenerative intervention. However, the significance of such CSC populations remains heavily debated. Using single-cell mRNA sequencing and genetic lineage tracing, we interrogate the existence of CSCs with unbiased mouse models of proliferation. Cycling cardiomyocytes were only robustly observed in the early postnatal growth phase, while cycling cells in homoeostatic and damaged adult myocardium consisted mainly of various noncardiomyocyte cell types. Injury-activated cardiac fibroblasts that acquire a gene expression profile similar to that of neonatal cardiac fibroblasts signal—in an autocrine fashion—to prevent cardiac rupture. We find no evidence for the existence of a quiescent CSC population.

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