Silver nanoparticles inhibit neural induction in human induced pluripotent stem cells

Abstract

Silver nanoparticles (AgNPs) have been widely used as consumer products due to their antibacterial activities. Despite their extensive use, AgNPs have been reported to cause various types of cytotoxicity, including neurotoxicity. However, the potential action of AgNPs on early fetal development has not been elucidated. This study determined the effects of AgNPs on neural induction in human induced pluripotent stem cells (iPSCs), used as a model for human fetal stage development. It was observed that exposure to AgNPs reduced the expression of several neural differentiation marker genes, including OTX2, an early biomarker for neurogenesis in iPSCs. Since neural differentiation requires ATP as a source of energy, the intracellular ATP content was also measured. It was observed that AgNPs decreased intracellular ATP levels in iPSCs. Since AgNPs suppressed energy production, a critical mitochondrial function, the effects of AgNPs on mitochondrial dynamics were further studied. The results revealed that AgNPs induced mitochondrial fragmentation and reduced the level of mitochondrial fusion protein mitofusin 1 (Mfn1). Previously, we reported that knockdown of Mfn1 in iPSCs inhibited neural induction via OTX2 downregulation. This suggested that AgNPs could induce cytotoxicity, including neurodevelopmental toxicity, via Mfn1-mediated mitochondrial dysfunction in iPSCs. Thus, mitochondrial function in iPSCs can be used for assessing the cytotoxic effects associated with nanomaterials, including AgNPs.

Keywords:

• Induced pluripotent stem cells
• silver nanoparticles
• AgNPs
• neural induction
• mitofusin

Acknowledgements

This work was supported by a Health and Labor Sciences Research Grant from the Ministry of Health, Labor, and Welfare, Japan (#H25-Kagaku-Ippan-002 and H28-Kagaku-Ippan-003 to Y. K.), a Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science, and Technology, Japan (#26293056 and #26670041 to Y. K., #17K00576 to S. Y.), the Research on Regulatory Harmonization and Evaluation of Pharmaceuticals, Medical Devices, Regenerative and Cellular Therapy Products, Gene Therapy Products, and Cosmetics from Japan Agency for Medical Research and Development, AMED (JP17mk0104027 to Y. K.), and a grant from the Smoking Research Foundation (to Y. K.).

Disclosure statement

The authors declare that there are no conflicts of interest.