The application of silver nanoparticles (AgNPs) in consumer products has been increasing rapidly over the past decades. Therefore, in vitro models capable of accurately predicting the toxicity of AgNPs are much needed. Hepatocyte-like cells (HLCs) derived from human induced pluripotent stem cells (iPSCs) represent an attractive alternative in vitro hepatotoxicity model. Yet, the use of iPSC-derived HLCs (iPSC-HLCs) for the study of nanoparticle toxicity has not been reported so far. In the present study, transcriptomic changes induced by varying concentrations (5–25 μg/ml) of AgNPs were characterized in iPSC-HLCs after 24-h exposure. AgNPs caused concentration-dependent gene expression changes in iPSC-HLCs. At all the concentrations, members of the metallothionein (MT) and the heat shock protein (HSP) families were the dominating upregulated genes, suggesting that exposure to AgNPs induced oxidative stresses in iPSC-HLCs and as a result elicited cellular protective responses in the cells. Functional analysis showed that the differentially expressed genes (DEGs) were majorly involved in the biological processes of metabolism, response to stress, and cell organization and biogenesis. Ingenuity Pathway Analysis revealed that cancer was at the top of diseases and disorders associated with the DEGs at all concentrations. These results were in accordance with those reported previously on hepatoma cell lines and primary hepatocytes. Considering the advantages iPSC-HLCs have over other liver cell models in terms of unlimited supply, consistency in quality, sustainability of function in long-term culture, and, more importantly, affordability of donor specificity, the results of the current study suggest that iPSC-HLCs may serve as a better in vitro model for liver nanotoxicology.

在过去的几十年中，银纳米粒子 (AgNPs) 在消费品中的应用迅速增加。因此，非常需要能够准确预测 AgNPs 毒性的体外模型。源自人类诱导多能干细胞 (iPSC) 的肝细胞样细胞 (HLC) 代表了一种有吸引力的替代体外肝毒性模型。然而，迄今为止尚未报道使用 iPSC 衍生的 HLC (iPSC-HLC) 研究纳米颗粒毒性。在本研究中，iPSC-HLCs 暴露 24 小时后，由不同浓度（5-25 μg/ml）AgNPs 诱导的转录组变化被表征。AgNPs 在 iPSC-HLCs 中引起浓度依赖性基因表达变化。在所有浓度下，金属硫蛋白 (MT) 和热休克蛋白 (HSP) 家族的成员是主要的上调基因，表明暴露于 AgNPs 会诱导 iPSC-HLC 中的氧化应激，并因此引发细胞中的细胞保护反应。功能分析表明，差异表达基因（DEGs）主要参与代谢、应激反应、细胞组织和生物发生等生物学过程。Ingenuity Pathway Analysis 显示，在所有浓度的 DEGs 相关疾病和紊乱中，癌症处于首位。这些结果与先前报道的关于肝癌细胞系和原代肝细胞的结果一致。考虑到 iPSC-HLC 相对于其他肝细胞模型在无限供应、质量一致性、长期培养中功能的可持续性以及更重要的是供体特异性的负担能力方面的优势，