Mann David A
Cellular Dynamics International, Inc. , 525 Science Drive, Madison, WI 53711 , USA +1 608 310 5108 ;
Expert Opin Drug Metab Toxicol. 2015 Jan;11(1):1-5. doi: 10.1517/17425255.2015.981523. Epub 2014 Nov 11.
The need for more predictive in vitro toxicity models is a critical deficit in current preclinical pipeline safety evaluations. Current models employing tumor-derived cancer cell lines and isolated primary human hepatocytes (PHHs) afford an approximation of overt cytotoxicity but do not provide hepatotoxicity prediction owing to liabilities in metabolic activity along with phenotypic variability and instability in culture. Induced pluripotent stem cell-derived hepatocytes (iPSC-HCs) offer a long-term solution to accessing liver tissue from representative diverse as well as idiosyncratic patient populations and can be sourced indefinitely. iPSC-HCs are currently being evaluated as potential replacements for the existing cell models, but they have yet to prove superiority. It is acknowledged that iPSC-HCs are not functionally equivalent to PHHs and are somewhat mixed in terms of their gene expression profile, simultaneously displaying mature and immature markers in vitro. Combining iPSC-HCs with organotypic culture systems affords an opportunity to maximize the potential of both technologies where the cells benefit from more complex culture conditions while unlocking the potential of the culture systems by affording stability and reproducibility to provide the future of predictive in vitro toxicity models.
对更具预测性的体外毒性模型的需求是当前临床前管线安全性评估中的一个关键缺陷。目前使用肿瘤衍生癌细胞系和分离的原代人肝细胞（PHH）的模型可以近似评估明显的细胞毒性，但由于代谢活性方面的缺陷以及培养中的表型变异性和不稳定性，无法提供肝毒性预测。诱导多能干细胞衍生的肝细胞（iPSC-HC）为从具有代表性的不同以及特殊患者群体获取肝组织提供了一个长期解决方案，并且可以无限获取。目前正在评估iPSC-HC作为现有细胞模型的潜在替代品，但它们尚未证明具有优越性。人们认识到iPSC-HC在功能上与PHH并不等同，并且在基因表达谱方面有些混杂，在体外同时显示成熟和不成熟标记物。将iPSC-HC与器官型培养系统相结合，为最大限度发挥这两种技术的潜力提供了机会，其中细胞受益于更复杂的培养条件，同时通过提供稳定性和可重复性来释放培养系统的潜力，从而为预测性体外毒性模型的未来发展提供支持。
