Cellular Dynamics Poster Presentations
Blake D. Anson PhD, Arne Thompson, Tromondae Feaster PhD, Brian Jarecki PhD, Cellular Dynamics International, a FUJIFILM company, Madison, Wisconsin
The combined efforts of academic, pharmaceutical, and regulatory scientists in the large-scale Comprehensive In-Vitro Proarrhythmia assay (CiPA), Japan iPS Cardiac Safety Assessment (JiCSA), and Consortium for Safety Assessment using Human iPS Cells (CSAHi) consortia demonstrates the prominent role of human induced pluripotent stem cell (hiPSC)-cardiomyocytes across all sectors of research. As hiPSC-cardiomyocytes continue to evolve, it is imperative to understand their performance in relation to previously validated models and versions. This study used the CiPA compound collection and the multi-electrode array (MEA) platform to evaluate the responses of two generations of commercially available hiPSC-derived cardiomyocytes, iCell Cardiomyocytes2 and iCell Cardiomyocytes. Manufacturer protocols were followed to evaluate iCell Cardiomyocytes after 14 days in culture and iCell Cardiomyocytes2 at more convenient time points of 4 and 7 days in culture. Baseline beat rates of 46, 39, and 34 bpm were recorded for iCell Cardiomyocytes2 at 4 and 7 in culture and iCell Cardiomyocytes after 14 days in culture, respectively. The single channel blocking compounds mexilitine, nifedipine, E-4031, and JNJ-303 and the multi-channel blocking compounds flecainide, moxifloxicin, quinidine, and ranolazine produced quantifiable effects on cellular electrophysiology that were within ½ log across all three culture conditions and hiPSC-cardiomyocytes. Arrhythmic behavior was also detected at similar concentrations across all three culture conditions and hiPSC-cardiomyocytes. The concordance of the data indicate that despite small changes in beat rate, iCell Cardiomyocytes and iCell Cardiomyocytes2 behave similarly in chemical space and thus bridging studies should be sufficient when adopting new product iterations.
Coby Carlson, Michael Hancock, Arne Thomson, Blake Anson, David A. Mann,
Cellular Dynamics International, a FUJIFILM company, Madison, Wisconsin
Drug induced liver injury (DILI) is a leading cause of drug withdrawal and current preclinical models of toxicity do not accurately predict effects in humans. Development of more predictive in vitro model systems to identify hepatotoxicity early during drug development is critical to avoid DILI in the clinic. Human induced pluripotent stem cell (iPSC)-derived hepatocytes (iCell Hepatocytes 2.0) that exhibit high purity and sustained biologically relevant functions help to address these needs for hepatotoxicology. To demonstrate the utility of iCell Hepatocytes 2.0 (HC 2.0) in assessing drug-induced hepatotoxicity, we have demonstrated good viability over a 14 day assay window. We have tested HC 2.0 responses to a set of known hepatotoxins including: amiodarone, acetaminophen (APAP), troglitazone, nefazadone, chlorpromazine, and FCCP across a number of cell death readouts highlighting their capacity for mechanistic toxicity studies. In addition, the prolonged viability also enables chronic dosing in vitro, affording the potential to detect the effects of slow to form metabolites and also perform analyses at physiologically relevant concentrations over sustained exposure periods. The short term high concentration sensitivities observed were comparable to those seen with primary human hepatocytes. However, effects seen over 48 hr and 7 day dosing illustrate the potential of HC 2.0 for predictive in vivo/in vitro toxicity correlation. With the ability routinely access patient specific genotypes and also culture in 3D spheroids and in co-culture with other hepatic stellate cells, iPSC-derived Hepatocytes provide a biologically relevant human model system for investigating drug-induced liver injury in preclinical drug development.