Cardiac interstitial tetraploid cells that escape replicative senescence are found in rodents but not large mammals

Abstract

Ploidy for cardiomyocytes is well described but remains obscure in cardiac interstitial cells (CICs). Ploidy of c-kit+CICs (cCICs) were assessed using a combination of confocal, karyotypic, and flow cytometric assessments coupled with molecular and bioinformatic analyses. Fundamental differences were found between cultured rodent (rat, mouse) cCICs possessing mononuclear tetraploid (4n) content versus large mammal (human, swine) with mononuclear diploid (2n) content. In-situ analysis, confirmed with fresh isolates, revealed diploid content in cCICs from human and a mixture of diploid and tetraploid nuclei in mouse. Molecular assessment of the p53 signaling pathway provides a plausible explanation for escape from replicative senescence in rodent but not human cCICs. Single cell transcriptional profiling reveals distinctions between diploid versus tetraploid populations in mouse cCICs, alluding to functional divergences. Collectively, these data reveal fundamental species-specific biological differences in cCICs that could account for challenges in extrapolation of myocardial preclinical studies from rodent to large animal models.