Abstract 14276: Induced Pluripotent Stem Cell-Derived Cardiomyocytes Form Electrical Coupling with Native Myocardium Contributing to Functional Recovery in Rat Chronic Infarction Model

Introduction: Optimal delivery method of induced pluripotent stem cell (iPSc) into the heart has not been established; however, scaffold-free cell-sheet method has been shown to effectively deliver abundant functional cells, whereas functional integrations of implanted cell-sheet into native myocardium are not fully addressed. We here hypothesized that iPSc-derived cardiomyocytes (CM) implanted with cell-sheet method might form electrical coupling with the native myocardium contributing to functional recovery in chronic myocardial infarction. Methods: iPSc-CM of mouse origin was generated by culturing embryoid body. The chronic infarction model was generated by occluding the left coronary artery for 2 weeks in immunodeficient rats, which then underwent either implantation of cell-sheet generated by iPSc-CM, neonatal CM, fibroblast or skeletal myoblast over the infarct area, or sham operation (n=10 each) with the effects assessed until 14 days post-treatment. Results: Daily electrical mapping of the heart surface using 64-channel multi-electrode probe uncovered that the iPSs-CM and the neonatal-CM treatment induced multiple ectopic excitations, which were not connected to the native myocardial electrical current, over the cell-sheet implanted area until 2 days. Interestingly, from 3 days onwards, ectopic excitations disappeared and magnitude of myocardial electrical current increased following the iPSc-CM or the neonatal-CM treatment, suggesting that electrical stimuli of the native heart were properly transferred into the cell-sheet. Consistently, left ventricular ejection fraction (LVEF) and activation recovery interval (ARI) of the iPSc (54%, 68 ms) and the neonatal CM treatment (54%, 71 ms) were significantly improved at 3 days compared to LVEF and ARI following the fibroblast (49%, 92 ms), the myoblast (49%, 89 ms) or the sham (48%, 96 ms). Electron microscopy and immunostaining identified the ultrastructure of the implanted iPSc-CM. Moreover the implanted iPSc-CM showed histological integration via desmosome. Conclusions: The iPSc-CM sheets may electrically integrate into the native myocardium in 3 days after implantation and contribute to functional recovery in rat myocardial infarction model.