Division of Toxicology, Office of Applied Research and Safety Assessment, Center for Food Safety and Applied Nutrition, U.S. Food and Drug Administration, Laurel, MD, 20708, USA.
Cell Biol Toxicol. 2021 Apr;37(2):245-259. doi: 10.1007/s10565-020-09529-1. Epub 2020 May 24.
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.
过去几十年，银纳米粒子（AgNPs）在消费产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。源自人诱导多能干细胞（iPSC）的肝样细胞（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）来研究纳米颗粒毒性。在本研究中，研究了在 24 小时暴露于不同浓度（5-25μg/ml）AgNPs 后 iPSC-HLC 中引起的转录组变化。AgNPs 在 iPSC-HLC 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）家族的成员都是上调基因的主要调控因子，这表明 AgNPs 暴露在 iPSC-HLC 中引起氧化应激，并导致细胞内保护性反应。功能分析表明，差异表达基因（DEGs）主要参与代谢、应激反应以及细胞组织和生物发生的生物学过程。Ingenuity 通路分析显示，在所有浓度下，癌症是与 DEGs 相关的疾病和失调的首要原因。这些结果与先前在肝癌细胞系和原代肝细胞中报道的结果一致。考虑到 iPSC-HLC 在其他肝细 胞模型中具有无限供应、质量一致性、长期培养功能的可持续性，以及更重要的是供体特异性的可负担性方面的优势，当前研究的结果表明，iPSC-HLC 可能成为更好的肝脏纳米毒理学体外模型。
