Leveraging the potential of human iPSC-derived cardiomyocytes

The ability to generate cardiomyocytes from human induced pluripotent stem cells (hiPSCs) provides unprecedented opportunities in the study and treatment of cardiac diseases. The objective of this dissertation is the development of novel methods of utilizing hiPSC-derived cardiomyocytes (hiPSC-CMs). First, we leveraged the potential of hiPSC-CMs to model congenital heart disease caused by mutations in the transcription factor ZIC3. We developed a method to directly explore the effect of ZIC3 inhibition using hiPSCs at a molecular, cellular, and functional level through utilization of CRISPR interference. Our results identified the role of ZIC3 in regulating Nodal signaling, Wnt signaling, and cell structure and motility processes during cardiac development, suggesting that ZIC3 mutation leads to congenital heart disease in humans by the abnormal regulation of multiple steps during left-right axis establishment. Next, we leveraged the potential of hiPSC-CMs to treat myocardial infarction. We demonstrated that the extended delivery of extracellular vesicles secreted by hiPSC-CMs could attenuate injury and promote recovery of the heart after infarction by regulating apoptosis and inflammatory pathways. These results suggest that hiPSC-CM secreted extracellular vesicles represent a novel cell free tool in the treatment of myocardial infarction and the understanding of heart recovery.