Abstract
Cardiomyocyte ploidy has been described but remains obscure in cardiac interstitial cells. Ploidy of c-kit+ cardiac interstitial cells was assessed using confocal, karyotypic, and flow cytometric technique. Notable differences were found between rodent (rat, mouse) c-kit+ cardiac interstitial cells possessing mononuclear tetraploid (4n) content, compared to large mammals (human, swine) with mononuclear diploid (2n) content. In-situ analysis, confirmed with fresh isolates, revealed diploid content in human c-kit+ cardiac interstitial cells and a mixture of diploid and tetraploid content in mouse. Downregulation of the p53 signaling pathway provides evidence why rodent, but not human, c-kit+ cardiac interstitial cells escape replicative senescence. Single cell transcriptional profiling reveals distinctions between diploid versus tetraploid populations in mouse c-kit+ cardiac interstitial cells, alluding to functional divergences. Collectively, these data reveal notable species-specific biological differences in c-kit+ cardiac interstitial cells, which could account for challenges in extrapolation of myocardial from preclinical studies to clinical trials.
Highlights
Cardiomyocyte ploidy has been described but remains obscure in cardiac interstitial cells
In situ ploidy analysis was performed through quantification of diamidino-2-phenylindole (DAPI) fluorescence intensity of reconstructed confocal z-stacks[34]
Ploidy grouping was determined by frequency of cells within fluorescence intensity ranges and results reported in aggregate from multiple patients and experiments (Fig. 1f)
Summary
Cardiomyocyte ploidy has been described but remains obscure in cardiac interstitial cells. Single cell transcriptional profiling reveals distinctions between diploid versus tetraploid populations in mouse c-kit+ cardiac interstitial cells, alluding to functional divergences. Several beneficial traits have emerged to account for initiation of polyploidization including adaptation to environmental stress, cell cycle regulation, DNA damage resistance, abrogation of senescence and apoptosis, tissue repair, and regeneration[5,7]. Many of these examples occur in plants and invertebrate species where regenerative capabilities are biologically normal (plants regenerate from cuttings, planaria can be cut into half and regenerate[1,2]). Regenerative tissues in the adult human body, including liver, skeletal muscle, and skin, all possess polyploid cellular populations
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