Abstract 10132: Human Ipsc Derived Cardiac Tissue Matured by Spontaneous Traveling Waves for Improved Drug Assessment

Abstract

Introduction: The precise evaluation of safety and efficacy for newly developed medication is of vital importance for drug discovery. As a promising candidate for the drug assessment, the human iPSC derived cardiomyocytes (hiPSC-CMs) tend to be less mature than adult cardiomyocytes, which could limit their application. We developed spontaneous traveling waves (TW) to rapidly pace and mature hiPSC-CMs. We hypothesized that the TW-matured hiPSC-CMs could serve as a more accurate model for drug discovery and development. Method and Results: The silicone wells and pillars were mounted in petri dishes. hiPSC-CMs were plated into the wells to form close-loop tissue where TW originated and paced the CMs in most of the wells (83.33 ± 13.6%, 18 wells from 3 tests). After 14-day culture, the hiPSC-CMs were evaluated by immunostaining, gene expression, western blotting and electron microscopy. Micro electrode array (MEA) were used to evaluate the drug response of CMs. The TW paced the CMs to beat at a much higher rate than the group without TW (TW: 220 ± 74 bpm vs. Control: 32.4 ± 30.1 bpm, n = 18, p < 0.0001, at day 6). After 14 day culture, TW group has significantly higher expression of myosin heavy chain beta, connexin 43, and myoglobin. Electron microscopy indicated TW CMs with larger sarcomeric bundles, well-defined Z disks and myofibrils. In addition, the TW group showed shortened QT interval, more close to the human adult level (female/male: 288 ± 21 and 237 ± 8 ms) than control group (TW: 280 ± 71 ms vs. Control: 460 ± 120 ms, n = 8, p = 0.0018). Moreover, TW group showed enhanced response to the β adrenoceptor agonist ( beat rate with 10 uM isoproterenol : TW: 111.1 ± 15.57 bpm vs. Control: 83.73 ± 10.92 bpm, n = 6, p = 0.0064 ). TW group showed significantly different response to sodium channel blocker and reduced data variation than control ( QT interval at 100 μM mexiletine: TW: 424.4 ± 74.7 ms, CV = 17.6% vs. Control: 694.57 ± 198.38 ms, CV = 28.6%, n = 4, p = 0.035). Conclusion: By creating the close-loop cardiac tissue, the traveling wave could spontaneously originate and rapidly pace hiPSC-CMs. The TW paced hiPSC-CMs showed improved sarcomeric and functional maturation, improved drug response with reduced data variation, holding potential as a robust and accurate candidate for drug discovery.