PDF(Pubmed)
Abstract：
The process of identifying and approving a new drug is a time-consuming and expensive procedure. One of the biggest issues to overcome is the risk of hepatotoxicity, which is one of the main reasons for drug withdrawal from the market. While animal models are the gold standard in preclinical drug testing, the translation of results into therapeutic intervention is often ambiguous due to interspecies differences in hepatic metabolism. The discovery of human induced pluripotent stem cells (hiPSCs) and their derivatives has opened new possibilities for drug testing. We used mesenchymal stem cells and hepatocytes both derived from hiPSCs, together with endothelial cells, to miniaturize the process of generating hepatic organoids. These organoids were then cultivated in vitro using both static and dynamic cultures. Additionally, we tested spheroids solely composed by induced hepatocytes. By miniaturizing the system, we demonstrated the possibility of maintaining the organoids, but not the spheroids, in culture for up to 1 week. This timeframe may be sufficient to carry out a hypothetical pharmacological test or screening. In conclusion, we propose that the hiPSC-derived liver organoid model could complement or, in the near future, replace the pharmacological and toxicological tests conducted on animals.
摘要：
识别和批准新药的过程是耗时且昂贵的程序。要克服的最大问题之一是肝毒性的风险，这是药品退出市场的主要原因之一。虽然动物模型是临床前药物测试的黄金标准，由于肝脏代谢的种间差异,将结果转化为治疗干预通常不明确.人类诱导多能干细胞（hiPSCs）及其衍生物的发现为药物测试开辟了新的可能性。我们使用了来自hiPSCs的间充质干细胞和肝细胞，连同内皮细胞，小型化肝类器官的生成过程。然后使用静态和动态培养物体外培养这些类器官。此外,我们测试了仅由诱导肝细胞组成的球体。通过使系统小型化，我们证明了维持类器官的可能性，但不是球体，在文化长达1周。该时间范围可能足以进行假设的药理学测试或筛选。总之,我们认为hiPSC衍生的肝脏类器官模型可以补充或，在不久的将来,取代对动物进行的药理和毒理学试验。
