HiPSC-derived multi-organoids-on-chip system for safety assessment of antidepressant drugs

作者：Fangchao Yin, Xu Zhang, Li Wang, Yaqing Wang, Yujuan Zhu, Zhongyu Li, Tingting Tao, Wenwen Chen, Hao Yu, Jianhua Qin · 发表于：Lab on a Chip · 年份：2020 · DOI：10.1039/d0lc00921k · 被引用次数：137 · 研究领域：3D Printing in Biomedical Research、Neuroscience and Neural Engineering、Microfluidic and Capillary Electrophoresis Applications

The poor predictive power of existing preclinical models has spurred efforts to develop human-relevant models for accurate assessment of drug safety. In this work, we developed a multi-organoids-on-a-chip system derived from human induced pluripotent stem cells (hiPSCs), which allows for the assessment of the cardiac safety of an antidepressant drug, following liver metabolism in vitro. This liver-heart organoids-on-chip device contains compartmentalized chambers separated by a porous membrane, which permits the co-culture of 3D human liver organoids in the upper multi-well chamber and cardiac organoids in the bottom micropillar array simultaneously. The co-cultured liver and heart organoids on chip maintained good viability and human organ-specific functions respectively, including the synthesis of albumin and urea of liver organoids, and the beating function of cardiac organoids. In particular, the liver organoids displayed proper metabolic capabilities with high expression of CYP450 enzyme genes. Clomipramine, a widely used antidepressant drug, can be metabolized into an active metabolite (desmethylclomipramine) through the hepatic CYP450 enzymes of liver organoids on chip identified by mass spectrometry. After exposure to 1 μM clomipramine in the liver chamber for 24 h and 48 h, the co-cultured heart organoids in the bottom layer showed significantly reduced cell viability, impaired functions of cardiac beating and calcium flux, indicating the hepatic metabolism-dependent...