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

• Type of Material: Article
• Authors: Kathleen M. Broughton, San Diego State University; Tiffany Khieu, San Diego State University; Nicky Nguyen, San Diego State University; Michael Rosa, San Diego State University; Sadia Mohsin, Temple University; Pearl Quijada, San Diego State University; Bingyan J. Wang, San Diego State University; Oscar H. Echeagaray, San Diego State University; Dieter A. Kubli, San Diego State University; Taeyong Kim, San Diego State University; Fareheh Firouzi, San Diego State University; Megan M. Monsanto, San Diego State University; Natalie A. Gude, San Diego State University; Robert M. Adamson, Sharp Memorial Hospital; Walter P. Dembitsky, Sharp Memorial Hospital; Michael Davis, Emory University; Mark A. Sussman, San Diego State University
• Language: English
• Date: 2019-06-13
• Publisher: Nature Research (part of Springer Nature): Fully open access journals
• Publication Version: Final Published Version
• Copyright Statement: © The Author(s) 2019
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1038/s42003-019-0453-z
• Title of Journal or Parent Work: Communications Biology
• ISSN: 2399-3642
• Volume: 2
• Start Page: 205
• End Page: 205
• Grant/Funding Information: K.M. Broughton is supported by NIH grant F32HL136196.; M.A. Sussman is supported by NIH grants R01HL067245, R37HL091102, R01HL105759, R01HL113647, R01HL117163, P01HL085577, and R01HL122525, as well as an award from the Fondation Leducq.
• Keywords: Heart stem cells
• Research Categories: Health Sciences, Medicine and Surgery; Engineering, Biomedical

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.