Abstract 18049: Chromosome Content of Cardiac Progenitor Cells Influences Regenerative Potential of the Heart

• Published in: Circulation (New York, N.Y.) Vol. 134; no. Suppl_1 Suppl 1; p. A18049
• Main Authors: Broughton, Kathleen, Khieu, Tiffany, Nguyen, Nicky, Mohsin, Sadia, Khubli, Dieter, Quijada, Pearl, Wang, Jessica, Monsanto, Megan, Gude, Natalie, Sussman, Mark
• Format: Journal Article
• Language: English
• Published: by the American College of Cardiology Foundation and the American Heart Association, Inc 11-11-2016
• ISSN: 0009-7322; 1524-4539

IntroductionDiscovery of endogenous stem cells in the heart, cardiac progenitor cells (CPC), has prompted intense basic discovery in multiple experimental animal models and clinical trials in heart failure patients. Animal or tissue models exhibiting regenerative properties are also characterized by cellular mononuclear genome duplication or polyploidization. Our lab identified a fundamental difference in mammalian CPCs ploidy between rodent (rat, mouse), possessing mononuclear tetraploid (4n) chromosome content, and large animal (human, swine), which are mononuclear diploid (2n). Ploidy differences prompt provocative questions regarding translational applicability of regenerative studies performed in rodents.HypothesisMononuclear chromatin duplication in CPCs improves regenerative capacity of the heart by overriding senescence-induced cell cycle arrest.Methods and ResultsPloidy content of cultured CPCs assessed by karyotype, confocal microscope, flow cytometry, and spectrometry was consistent and stable over increased passages with samples from eight humans (normal and heart failure), two swine strains (Gottingen and Yorkshire), six mouse strains (FVB, C57, CAST, SPRET, SAMP6, and SAMR1), and seven rat clonal lines (Sprague Dawley). Growth rates positively correlated with ploidy content, as rodent CPCs proliferate faster than human or swine CPCs and rodent CPCs proliferate faster with increased passages. Senescence in human CPCs occurs between passages 14-26, whereas rodent CPCs did not senesce (>100 passages). In comparison, diploid mouse ckit+ BMSCs senesce between passage 8-10. In situ ploidy analysis of ckit+ cells confirmed diploid content in human tissue and a mixture of mononuclear diploid and tetraploid DNA content in mouse. Freshly isolated mouse ckit+ cells from the heart verify a mixture of diploid and tetraploid DNA content.ConclusionThese findings provide further insight into the unique characteristics of different ckit+ cells found within the heart, the significance of ploidy in the biological capacity of the CPC, and the endogenous stem cell influence on the regenerative capacity of the heart. Future studies focus upon the advantage of polyploid content in mediating myocardial regeneration.