Assessment of long-term functional maintenance of primary human hepatocytes to predict drug-induced hepatoxicity in vitro
Assessment of long-term functional maintenance of primary human hepatocytes to predict drug-induced hepatoxicity in vitro
复制标题
评估原代人肝细胞的长期功能维持以预测体外药物引起的肝毒性
DOI：
10.1007/s00204-021-03050-y
复制
发表时间：
2021-04-14
影响因子：
6.1
通讯作者：
Yan, Hexin
中科院分区：
文献类型：
--
作者：
Chen, Yi;Tang, Dan;Yan, Hexin
肝细胞是肝脏的主要细胞成分，并执行代谢，解毒和内分泌功能。功能性肝细胞在肝脏疾病的药物开发、毒性评价和细胞治疗中具有重要价值。近年来，越来越多的体外模型被开发用于筛选药物和测试其毒性。然而，在体外长时间维持肝细胞功能是一个严峻的挑战。即使是新鲜分离的肝细胞培养很短的时间可能会失去功能，通过自发去分化。因此，新的细胞培养系统，允许延长肝细胞的维护和更预测的长期体外研究是必要的。在这项研究中，我们开发了一个条件培养系统组成的小分子组合，可以保持肝细胞的形态和功能，在长期。原代培养2个月的人肝细胞显示，条件培养基能够稳定地保持肝脏功能，如白蛋白和α-抗胰蛋白酶分泌、肝脏转运活性、尿素合成和氨消除。此外，该培养模型可用于体外评估药物诱导的肝毒性。总之，我们的工作提出了一种可行的方法来维持肝细胞功能在体外，并提出了一个有前途的模型，长期毒理学研究和药物开发。
Hepatocytes are the main cell components of the liver and perform metabolic, detoxification, and endocrine functions. Functional hepatocytes are of great value in drug development, toxicity evaluation, and cell therapy for liver diseases. In recent years, an increasing number of in vitro models have been developed to screen drugs and test their toxicity. However, maintaining hepatocyte function in vitro for a long time is a serious challenge. Even freshly isolated liver cells cultured for a short time may lose function via spontaneous dedifferentiation. Thus, novel cell culture systems allowing extended hepatocyte maintenance and more predictive long-term in vitro studies are required. In this study, we developed a conditioned culture system composed of a small-molecule combination that can maintain hepatocyte morphology and functions over the long term. Two-month culture of primary human hepatocytes showed that the conditioned medium was able to stably preserve hepatic functions such as albumin and α-antitrypsin secretion, hepatic transport activity, urea synthesis, and ammonia elimination. Furthermore, this culture model can be used to assess drug-induced hepatotoxicity in vitro. In summary, our work suggests a feasible approach to maintain hepatocyte function in vitro and proposes a promising model for long-term toxicological studies and drug development.