Introduction and hypothesis: A functional cardiac tissue “patch” constituted with human induced pluripotent stem cells (hiPSCs) derived cardiac cells was found to integrate in and facilitate regeneration of an infarct-damaged heart muscle in rodents. Here, we utilized a swine model of acute myocardial infarction (MI) to investigate the therapeutic impact of large tissue engineered human cardiac muscle patch (hCMP) transplantation and elucidate the underlying mechanisms.
Methods: Female swines were randomly assigned to four experimental groups prior to surgical procedure: sham-operated group (n=11), MI only group (n=14), MI and patch only group (n=14, MI followed by two acellular fibrin patches), and MI and tri-lineage cell patch group (n=13, MI followed by two fibrin patches containing of hiPSC-derived cardiomyocytes, endothelial cells, and smooth muscle cells). Following a 60 minutes of ligation of left descending coronary artery, the patches were applied to the ischemia area of the swine heart. Cardiac function and infarction size were determined via magnetic resonance imaging. Engraftment rate, cell structure, apoptosis, and vasculogenic response were assessed by histology.
Results:In vivo, the structural staining and functional assessments, including conductive velocity, calcium transients, micro-impedence, and force generation indicated that the cells in hCMPs have a good electrical communication and maturation characters. Four weeks post patch transplantation, animals receiving tri-lineage cell patches showed alleviated cardiac hypertrophy, improved cardiac function, and reduced infarct size comparing to animals receiving acellular patches. Histological analysis showed large engraftment with well-organized sarcomeric structure and gap junction formation, and new vessel formation from hiPSC-derived cardiovascular cells. Cell patch transplantation also significantly improved left ventricular arteriole density and cell apoptosis without inducing ventricular arrhythmias.
Conclusion: Our findings in large animal model of MI demonstrate high therapeutic potential of bioengineered heart tissue, engineered from hiPSC-derived cardiac cells, for cardiac repair in human clinical applications.