Abstract 14033: Development of a Drug-induced Spiral Wave Re-entrant Tachycardia Model in Human Induced Pluripotent Stem Cell-derived Mini-3D Cardiac Tissue Sheets
Backgrounds: Life-threatening arrhythmias are critical issues in clinical health care. The development of human induced pluripotent stem cell (hiPSC)-derived arrhythmia models is advantageous for studying the mechanisms of arrhythmia and discovering therapeutic drugs. Nevertheless, in vitro models that can reproduce re-entrant arrhythmia are still under investigation. Here we report a drug-induced spiral wave re-entrant tachycardia model using hiPSC-derived Cardiac Tissue Sheets (CTSs).
Methods & Results: We induced cardiovascular cells including cardiomyocytes (CMs) and mesenchymal cells (MCs) from hiPSCs with a monolayer serum-free culture method. We generated CTSs, which formed a mini-3D structure, from purified and/or mixed populations of induced cardiovascular cells using 48 well-sized temperature-responsive culture dishes (UpCell; CellSeed, Tokyo, Japan). We monitored functions of these CTSs electrically with the Multi Electrode Device (MED) and optically with the Motion Vector Prediction (MVP). In the MED study, we found that these CTSs underwent prolongation of field potential duration induced by administration of an IKr channel blocker; E4031. With higher concentrations of E4031, these CTSs exhibited field potentials characteristic of persistent tachycardia. In the MVP study, re-entrant spiral wave propagation was observed in the CTSs that could potentially mimic the onset of re-entrant tachycardia. We compared the efficiency of tachycardia induction in sheets made from a cell population in which CMs and MCs were evenly mixed (CMs/MCs sheet), with that in sheets made from CMs only (CMs sheet). The tachycardia induction rate in the CMs/MCs sheets was 100% (n=15/15) while that in the CMs sheet was 0% (0/16) (p<0.0001). This result indicates that a massive reduction in the CM component within the CTSs tends to cause re-entrant tachycardia, possibly mimicking the pathology of end-stage cardiomyopathies.
Conclusion: We succeeded in creating valuable hiPSC-derived mini-3D CTSs which underwent spiral wave re-entrant tachycardias in vitro. These CTSs hold potential for a broad range of applications, including cardiac arrhythmia studies, drug discovery and drug safety tests.
Author Disclosures: M. Kawatou: None. H. Masumoto: None. H. Fukushima: None. G. Morinaga: None. K. Minakata: None. T. Ikeda: None. R. Sakata: None. T. Ashihara: None. Y. Sekino: None. J.K. Yamashita: Research Grant; Significant; Nippon Boehringer Ingelheim Co. Ltd. Other Research Support; Modest; Takara Bio Inc.. Ownership Interest; Modest; iHeart Japan Co.Ltd.
- © 2016 by American Heart Association, Inc.