Prediction of drug-induced immune-mediated hepatotoxicity using hepatocyte-like cells derived from human embryonic stem cells
Prediction of drug-induced immune-mediated hepatotoxicity using hepatocyte-like cells derived from human embryonic stem cells
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DOI：
10.1016/j.tox.2017.06.005
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发表时间：
2017-07-15
期刊：
影响因子：
4.5
通讯作者：
Lee, Seung-Hyo
中科院分区：
文献类型：
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作者：
Kim, Dong Eon;Jang, Mi-Jin;Lee, Seung-Hyo
药物性肝损伤（DILI）是肝脏疾病的主要原因，也是药物开发过程中的关键安全因素。除了药物特异性肝毒性的起始事件外，免疫应答失调也被认为是DILI的主要病理事件。因此，需要一种可靠的细胞培养模型来评估药物诱导的免疫反应，以预测药物开发的肝毒性。为此，干细胞衍生的肝细胞显示出巨大的潜力。在这里，我们报告，肝细胞样细胞来源于人胚胎干细胞（hES-HLC）可用于评估药物诱导的肝毒性免疫事件。用对乙酰氨基酚治疗显著提高了hES-HLC的炎性细胞因子水平。此外，当在从对乙酰氨基酚处理的hES-HLC获得的条件培养基中培养时，三种人免疫细胞系Jurkat、THP-1和NK 92 MI被激活。为了进一步验证，我们测试了噻唑烷二酮（TZD）类抗糖尿病药物，包括因严重特异质药物肝毒性而退出市场的曲格列酮。我们发现TZD药物治疗hES-HLCs导致促炎细胞因子的产生并最终导致相关的免疫细胞活化。总之，我们的研究首次证明了hES-HLC作为评估药物诱导以及免疫介导的肝毒性的体外模型系统的潜力。
Drug-induced liver injury (DILI) is a leading cause of liver disease and a key safety factor during drug development. In addition to the initiation events of drug-specific hepatotoxicity, dysregulated immune responses have been proposed as major pathological events of DILI. Thus, there is a need for a reliable cell culture model with which to assess drug-induced immune reactions to predict hepatotoxicity for drug development. To this end, stem cell-derived hepatocytes have shown great potentials. Here we report that hepatocyte-like cells derived from human embryonic stem cells (hES-HLCs) can be used to evaluate drug-induced hepatotoxic immunological events. Treatment with acetaminophen significantly elevated the levels of inflammatory cytokines by hES-HLCs. Moreover, three human immune cell lines, Jurkat, THP-1, and NK92MI, were activated when cultured in conditioned medium obtained from acetaminophen-treated hES-HLCs. To further validate, we tested thiazolidinedione (TZD) class, antidiabetic drugs, including troglitazone withdrawn from the market because of severe idiosyncratic drug hepatotoxicity. We found that TZD drug treatment to hES-HLCs resulted in the production of pro-inflammatory cytokines and eventually associated immune cell activation. In summary, our study demonstrates for the first time the potential of hES-HLCs as an in vitro model system for assessment of drug-induced as well as immune-mediated hepatotoxicity.