Abstract 15038: Transplantation of Genomic Integration-free Human iPS Cell-derived Cardiac Tissue Sheets Into Porcine Infarct Hearts Produced No Lethal Arrhythmia: A Preclinical Study for a Safer Human iPS Cell Therapy
Background: Any preclinical study of a human iPS cell(hiPSC)-based cardiac regenerative therapy must confirm that the therapy in question does not produce lethal arrhythmias. In a recent study, we succeeded in long-term (<9 months) tumor-free transplantation of genomic integration-free hiPSC-derived cardiac tissue sheets (CTS) into a rat myocardial infarction (MI) model. In the present study, we attempted to prove that the integration-free CTS do not produce life-threatening arrhythmias after transplantation into a porcine MI model. We chose porcine hearts because they have a heart rate similar to that of the human heart. METHODS & RESULTS: We induced a mixture of cardiomyocytes (CMs) and vascular cells (endothelial cells [ECs] and vascular mural cells [MCs]) from integration-free hiPSCs and generated CTSs using temperature-responsive culture dishes (UpCell, CellSeed, Tokyo, Japan). Self-pulsating CTSs were approximately 3.5cm diameter with approximately 7x106 of cells containing cTnT+ CMs (41±11.9%), VE-cadherin+ ECs (7.0±2.6%) and PDGFRβ+ MCs (32.7±25.0%). In the transplantation group (Tx group: n=4), we induced MI in microminipigs (13-21 months old) by two-stage ligation of the left anterior descending coronary artery, and transplanted CTSs at 2 weeks after MI induction (4 sheets per recipient heart) under immunosuppression. Neither arrhythmia-related sudden death nor tumor formation was observed in any transplanted animals during the observation period (8 weeks). In the Tx group, echocardiogram showed a significant improvement in systolic function of the left ventricle (fractional shortening: 36.7%±2.3 vs 25.2%±2.2, p<0.05, sham-operated animals [Sham]: n=3 ). Holter electrocardiogram showed no episode of ventricular tachycardia in the Tx group during the observation period, whereas 67% (2/3) of Sham exhibited ventricular tachycardia. In the Tx group, beat to beat variability of ventricular repolarization, a surrogate marker of ventricular tachycardia, was lower than that in the Sham (1.95±0.6 ms vs 3.65±0.47 ms). CONCLUSIONS: This preclinical study using genomic integration-free CTS indicated a promising feature of hiPSC-based cardiac regenerative therapy for clinical use.
- Regenerative medicine stem cells
- Ventricular arrhythmia
- Myocardial infarction
Author Disclosures: T. Aoki: None. H. Masumoto: None. H. Ohara: None. Y. Nakamura: None. H. Izumi-Nakaseko: None. K. Ando: None. T. Ikuno: None. M. Kawatou: None. M. Ishigami: None. K. Minakata: None. T. Ikeda: None. A. Sugiyama: None. J. Yamashita: Research Grant; Significant; iHeart Japan Inc., Takara Bio Inc., Boehringer Ingelheim Japan. Ownership Interest; Significant; Founder and stock holder of iHeart Japan Inc.. R. Sakata: None.
- © 2015 by American Heart Association, Inc.