Abstract
Mammalian hearts lose their regenerative potential shortly after birth. Stimulating the proliferation of preexisting cardiomyocytes is a potential therapeutic strategy for cardiac damage. In a previous study, we identified 30 compounds that induced the bona-fide proliferation of human iPSC-derived cardiomyocytes (hiPSC-CM). Here, we selected five active compounds with diverse targets, including ALK5 and CB1R, and performed multi-omic analyses to identify common mechanisms mediating the cell cycle progression of hiPSC-CM. Transcriptome profiling revealed the top enriched pathways for all compounds including cell cycle, DNA repair, and kinesin pathways. Functional proteomic arrays found that the compounds collectively activated multiple receptor tyrosine kinases including ErbB2, IGF1R, and VEGFR2. Network analysis integrating common transcriptomic and proteomic signatures predicted that MAPK/PI3K pathways mediated compound responses. Furthermore, VEGFR2 negatively regulated endoreplication, enabling the completion of cell division. Thus, in this study, we applied high-content imaging and molecular profiling to establish mechanisms linking pro-proliferative agents to mechanisms of cardiomyocyte cell cycling.