Abstract
Contractility of the adult heart relates to the architectural degree of sarcomeres in individual cardiomyocytes (CMs) and appears to be inversely correlated with the ability to regenerate. In this study we utilized multiple imaging techniques to follow the sequence of sarcomere disassembly during mitosis resulting in cellular or nuclear division in a source of proliferating human pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). We observed that both mono- and binuclear hiPSC-CMs give rise to mononuclear daughter cells or binuclear progeny. Within this source of highly proliferative hiPSC-CMs, treated with the CHIR99021 small molecule, we found that Wnt and Hippo signaling was more present when compared to metabolic matured non-proliferative hiPSC-CMs and adult human heart tissue. Furthermore, we found that CHIR99021 increased the efficiency of non-viral vector incorporation in high-proliferative hiPSC-CMs, in which fluorescent transgene expression became present after the chromosomal segregation (M phase). This study provides a tool for gene manipulation studies in hiPSC-CMs and engineered cardiac tissue. Moreover, our data illustrate that there is a complex biology behind the cellular and nuclear division of mono- and binuclear CMs, with a shared-phenomenon of sarcomere disassembly during mitosis.
Highlights
The contractile tissue of the heart is composed of a mixture of different cells, including approximately 35% cardiomyocytes (CMs) [1]
These results indicate that sarcomere breakdown, by reduced Troponin T lines, is present in human-induced pluripotent stem cells (hiPSCs)-CMs that undergo cytokinesis
Previous studies have shown a correlation between the amount of diploid CMs and substantial regenerative capacity, raising the hypothesis that multinucleation and/or polyploidy forms a block for CM proliferation and heart regeneration [9,10,25,29,30]
Summary
The contractile tissue of the heart is composed of a mixture of different cells, including approximately 35% cardiomyocytes (CMs) [1]. Higher sarcomere architectural organization is related to maturity of the heart [2], while immature organization of sarcomeres correlates to the capacity of CMs to proliferate [3]. Previous studies in rodent hearts have shown that during embryonic and early postnatal hyperplastic growth phases the CMs gradually disassemble their sarcomeres during mitosis to ensure cytokinesis [4,5,6]. The hypertrophic growth dynamic is accompanied by increased ploidy and multinucleation of the adult heart [9,10]. The exact dynamics of human CM multinucleation and self-duplication in relation to sarcomere architecture remain largely unknown. Reliable determination of CM cytokinesis, multinucleation, self-duplication and nuclear ploidy is challenging [11,12,13]
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