Abstract 194: Frequency of Mononuclear Diploid Cardiomyocytes Underlies Natural Variation in Heart Regeneration

Abstract

Strong evidence from the literature supports the model that mononuclear, diploid cardiomyocytes (MNDCMs), a relatively rare population in the adult mammalian heart, are a regeneration-competent population, but this has not previously been subjected to experimental analysis. This project explores the hypothesis that the frequency of MNDCMs in the adult mammalian heart and regenerative potential are two interlinked, variable traits determined by multiple genetic parameters. If so, different individuals will have varying capacity to undergo heart regeneration following injury based on their unique genetic backgrounds. By surveying 120 inbred mouse strains, we found that the percentage of mononuclear cardiomyocytes in the adult mouse heart is a polygenic trait that is surprisingly variable (2.3%-17.0%). We confirmed experimentally that the degree of functional recovery and cardiomyocyte proliferation after permanent coronary artery ligation correlates with MNDCM content. Using genome-wide association, we identify Tnni3k as one gene with natural alleles that influence variation in this composition, and show in an isogenic strain background that Tnni3k knockout results in elevated MNDCM content and elevated cardiomyocyte proliferation after injury. Reciprocal to mammals, zebrafish are known to retain an almost pure MNDCM population through adulthood and are able to efficiently regenerate after adult heart injury. Here, we show that overexpression of Tnni3k in zebrafish promotes cardiomyocyte polyploidization and compromises heart regeneration, indicating a commonality in the regenerative process between the two species. Our results provide support for the requirement of the resident mononuclear diploid subpopulation of cardiomyocytes in heart regeneration. Moreover, our results imply that intrinsic heart regeneration is not uniform and limited in all individuals, but rather is a variable trait subject to the influence of multiple genes.