Abstract 14635: Highly Purified Human iPS Cell Derived Cardiomyocyte Cell Sheet Improves Cardiac Function Through Electromechanical Integration in Porcine Ischemic Cardiomyopathy Model - a Preclinical Trial for Myocardial Regeneration Therapy
Introduction Human iPS cell derived cardiomyocytes(hiPS-CMs) is a promising cell source in regenerating myocardium. However, several issues exist for clinical translation, including how to obtain and purify large number of hiPS-CMs, to exclude possible teratoma formation and whether hiPS-CMs can electromechanically connect native myocardium or not. Scaffold-free cell sheet have been developed as one of the best methods to transplant abundant cells without cell loss or damage. We hypothesized that our culture system may provide large amount of hiPS-CMs with high purity and that hiPS-CMs sheet transplantation may improve cardiac function in ischemic cardiomyopathy (ICM).
Methods & Results Human iPS cells were established by introducing the retrovirus containing Oct3/4, Sox2, Klf4 and c-Myc into human dermal fibroblast. Treatment by WNT signaling molecules induced cardiomyogenic differentiation, yielding 1.2x107 hiPS-CMs which showed more than 90% positive for α-actinin, Nkx2.5 and cardiac troponin T. We created four hiPS-CMs sheets using thermoresponsive dishes. They were transplanted over the infarct myocardium of ICM model induced by placing ameroid constrictor on LAD in porcine (iPS group=5: sheet transplantation with daily FK506 intake, Sham group=5). On echocardiography, cardiac performance of iPS group was significantly better than that of Sham group at 8 weeks after transplantation (EF;53±8% vs 36±6%, P<0.05, LVDs; 25±2mm vs 36±5mm, P<0.05). There was no significant difference in LVDd between 2 groups. Premature ventricular contractions were rarely detected by Holter ECG. Epicardial activation patterns by epicardial mapping were improved in iPS group, which indicate that iPS-CMs electrically integrated with native myocardium. Teratoma was not identified in any sample and human derived cells were detected in transplanted area by in-situ hybridization of human chromosome.
Conclusion Clinical applicable hiPS cell culture system was established and hiPS-CMs sheet could integrate with host myocardium electromechanically, leading to functional recovery without teratoma formation or life-threatening arrhythmias. These data suggest that hiPS-CMs sheet provide therapeutic effects on severe heart failure in clinical setting.
- © 2011 by American Heart Association, Inc.