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bioRxiv · 10.1101/521716

Tetraploidy in rodent cardiac stem cells confers enhanced biological properties

Broughton, K.·Khieu, T.·Nguyen, N.·Rosa, M.·Mohsin, S.·Quijada, P.·Wang, J.·Echeagaray, O.·Kubli, D.·Kim, T.·Firouzi, F.·Monsanto, M.·Gude, N.·Adamson, R.·Dembitsky, W.·Davis, M.·Sussman, M.
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Abstract

Ploidy for cardiomyocytes is well described but remains obscure in cardiac interstitial cells (CICs). Ploidy of c-kit+CICs 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) c-kit+CICs 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 c-kit+CICs 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 ckit+CICs. Single cell transcriptional profiling reveals distinctions between diploid versus tetraploid populations in mouse ckit+CICs, alluding to functional divergences. Collectively, these data reveal fundamental species-specific biological differences in c-kit+CICs that could account for challenges in extrapolation of myocardial preclinical studies from rodent to large animal models.

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Broughton, K., Khieu, T., Nguyen, N., Rosa, M., Mohsin, S., Quijada, P., Wang, J., Echeagaray, O., Kubli, D., Kim, T., Firouzi, F., Monsanto, M., Gude, N., Adamson, R., Dembitsky, W., Davis, M., Sussman, M.. 2019-01-16. Tetraploidy in rodent cardiac stem cells confers enhanced biological properties. https://doi.org/10.1101/521716

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