Cardiac interstitial tetraploid cells can escape replicative senescence in rodents but not large mammals

• Published in: Communications biology Vol. 2; no. 1; p. 205
• Main Authors: Broughton, Kathleen M., Khieu, Tiffany, Nguyen, Nicky, Rosa, Michael, Mohsin, Sadia, Quijada, Pearl, Wang, Bingyan J., Echeagaray, Oscar H., Kubli, Dieter A., Kim, Taeyong, Firouzi, Fareheh, Monsanto, Megan M., Gude, Natalie A., Adamson, Robert M., Dembitsky, Walter P., Davis, Michael E., Sussman, Mark A.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 13-06-2019; Nature Publishing Group
• Subjects: 13; 13/100; 13/31; 13/51; 14; 14/19; 631/532/2118/2440; 631/532/2440; Animals; Biology; Biomedical and Life Sciences; c-Kit protein; Cardiomyocytes; Cell Proliferation; Cellular Senescence; Clinical trials; Colon; Diploids; Divergence; Down-Regulation; Female; Flow Cytometry; Gene Expression Profiling; Heart; Humans; Interstitial cells; Karyotyping; Leukocytes, Mononuclear - cytology; Life Sciences; Male; Mice; Microscopy, Confocal; Myocytes, Cardiac - metabolism; p53 Protein; Ploidies; Ploidy; Rats; Senescence; Signal Transduction; Stem Cells - cytology; Swine; Tetraploidy; Transcription; Heart stem cells
• ISSN: 2399-3642; 2399-3642
• DOI: 10.1038/s42003-019-0453-z

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.
Broughton et al. report differences between rodent and large mammals with respect to ploidy of the cardiac interstitial cell population. These species-specific differences in ploidy of cardiac interstitial cells suggest potential challenges in extrapolating myocardial preclinical studies from rodent to large mammals.