Effects of Pharmacological Polyploidization in Human iPSC-derived Cardiomyocytes
Cell polyploidization, an increase in cellular DNA content without cytokinesis, is closely linked with aspects of cellular function in various tissues and is a defining characteristic of postnatal heart development in many species. However, investigation into how polyploidy affects cardiomyocytes (CMs) has been limited. Despite these challenges, CM polyploidy has been directly shown to attenuate proliferation in zebrafish CMs and diploid CM abundance correlates with recovery following coronary artery ligation in mice, highlighting the importance of understanding this biological process in CMs. In this study, we generated polyploid hiPSC-CMs via inhibition of Aurora Kinase B and found this results in increased cell size, reduced baseline cycling rates and responsiveness to mitogenic stimuli, affected the overall transcriptome and rates of transcription and translation, and altered CM Ca2+ handling. Our work suggests that CM polyploidy may not be just an outcome of CM maturation, but rather it serves a functional purpose. Further examination of the differences between diploid and polyploid hiPSC-CMs can expand our understanding of postnatal CM development and how polyploidy impacts CM growth and maturation. Overall design: Human iPSC-derived cardiomyocytes were treated with either the small molecule AZD1152, which inhibits Aurora Kinase B (AURKBi, 100nM) or vehicle control, for 4d starting when the hiPSC-CMs were day 16-20 post initiation of differentiation. The CMs were then fed normally for 7d without drug, and collected for bulk RNA sequencing.