Stem cell-derived models to improve mechanistic understanding and prediction of human drug-induced liver injury.
Stem cell-derived models to improve mechanistic understanding and prediction of human drug-induced liver injury.
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干细胞衍生的模型，以提高对人类药物诱导的肝损伤的机械理解和预测。
DOI：
10.1002/hep.28886
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发表时间：
2017-02
期刊：
影响因子：
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通讯作者：
Park BK
中科院分区：
文献类型：
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作者：
Goldring C;Antoine DJ;Bonner F;Crozier J;Denning C;Fontana RJ;Hanley NA;Hay DC;Ingelman-Sundberg M;Juhila S;Kitteringham N;Silva-Lima B;Norris A;Pridgeon C;Ross JA;Young RS;Tagle D;Tornesi B;van de Water B;Weaver RJ;Zhang F;Park BK
目前的临床前药物测试并不能预测人体中某些形式的药物不良反应。提高药物诱导的人体组织损伤的可预测性的努力包括使用干细胞技术来产生用于筛选药物在人体中的不良作用的人体细胞。诱导多能干细胞的出现意味着最终有可能开发个性化毒理学，以确定个体间对药物不良反应的易感性。然而，特异质药物诱导的肝损伤（DILI）的复杂性意味着目前没有任何单细胞模型，无论是原代肝组织来源的，来自肝细胞系的，还是来自干细胞的，都不能充分模拟人类DILI期间发生的情况。然而，模拟肝细胞关键特征的人类肝细胞的单细胞模型可能在评估潜在化学风险方面很有价值;此外，了解如何生成相关肝细胞对于构建复杂的多细胞肝脏模型也至关重要。目前，从干细胞分化的肝细胞样细胞仍然不能重现完全成熟的肝细胞表型。因此，我们召集了来自临床前和临床肝毒性和安全性评估领域的多位专家，来自行业、学术界和监管机构，专门探讨干细胞在肝毒性安全性评估中的应用，并对未来的发展方向提出建议。在这篇简短的综述中，我们特别讨论了使用定义的表型将干细胞衍生的肝细胞样细胞与其终末分化的人类对应物进行基准测试的重要性，以确保细胞在实验室之间具有相关性和可比性，并概述了为什么在将细胞引入化学安全性评估之前，这个过程是必不可少的。
Current preclinical drug testing does not predict some forms of adverse drug reactions in humans. Efforts at improving predictability of drug-induced tissue injury in humans include using stem cell technology to generate human cells for screening for adverse effects of drugs in humans. The advent of induced pluripotent stem cells means that it may ultimately be possible to develop personalised toxicology to determine inter-individual susceptibility to adverse drug reactions. However, the complexity of idiosyncratic drug-induced liver injury (DILI) means that no current single cell model, whether of primary liver tissue origin, from liver cell lines, or derived from stem cells, adequately emulates what is believed to occur during human DILI. Nevertheless, a single cell model of a human hepatocyte which emulates key features of a hepatocyte is likely to be valuable in assessing potential chemical risk; furthermore understanding how to generate a relevant hepatocyte will also be critical to efforts to build complex multicellular models of the liver. Currently, hepatocyte-like cells differentiated from stem cells still fall short of recapitulating the full mature hepatocellular phenotype. Therefore, we convened a number of experts from the areas of preclinical and clinical hepatotoxicity and safety assessment, from industry, academia and regulatory bodies, to specifically explore the application of stem cells in hepatotoxicity safety assessment, and to make recommendations for the way forward. In this short review, we particularly discuss the importance of benchmarking stem cell-derived hepatocyte-like cells to their terminally-differentiated human counterparts using defined phenotyping, to make sure the cells are relevant and comparable between labs, and outline why this process is essential before the cells are introduced into chemical safety assessment.