Hepatocytes - "Comprehensive impedance-based hepatotoxicity assay for metabolically active iPSC-derived hepatocytes"
Hepatotoxicity and drug-induced liver injury (DILI) are Hepatotoxicity and drug-induced liver injury (DILI) are leading reasons for drug failure to market, leading to approximately 18% of market withdrawals of drugs in the last decade. Additionally, only half of drugs with a potential to induce hepatotoxicity are actually identified during preclinical animal studies. This highlights the importance of generating more advanced cell-based models and experimental strategies to enhance the predictivity of these assays. Current existing in vitro models employed to predict DILI mostly focus on hepatocytes, though primary hepatocytes do not maintain their phenotype. iCell® Hepatocytes 2.0 (FUJIFILM CellularDynamics, FCDI) are human iPSC-derived cells with a wide variety of basic and functional characteristics which make them amenable to applications such as compound-mediated ADME-T and DILI toxicity. In addition to displaying characteristic hepatocyte morphology,(i.e., polygonal shape, polynucleation and formation of bile canalicular channels), these cells also express liver cell markers, including albumin, A1AT, and HNF4a, and exhibit basic and induced P450 functions, as observed in primary human hepatocytes. iCell® Hepatocytes 2.0maintain morphology, marker expression, and metabolic function in culture over a longer time frame compared to primary human hepatocytes, rendering these cells useful for investigations of acute and chronic DILI responses in a 2D culture system using impedance. Combining these cells with the planar gold-film electrodes on the CardioExcyte 96 reveal alterations in confluency, cell contact (morphological shape) and conductivity of adherent cells, thereby providing a measure of toxicity. Dose-dependent harmful effects of drugs could be evaluated over time in a functional 2D cell-based model without the need for 3D spheroid formation.