Impacts of Inorganic Arsenic Exposure on Genetic Stability of Human Mesenchymal Stromal Cells.

Abstract

Human mesenchymal stem/stromal cells (hMSCs) can differentiate into mesoderm-type cells, making them suitable candidates for tissue repair therapies. However, their relatively low frequency in adult tissue necessitates ex vivo expansion prior to regenerative medicine applications, and therefore, long-term hMSC genetic stability during expansion should be studied. hMSC applications in regenerative medicine ensure commercial availability of normal karyotype human primary cells for toxicity assessment and hMSCs could serve as alternatives to immortalized human cell models. In this work, we evaluated the potential of hMSCs in toxicity testing using inorganic arsenic (iAs) as a case study. hMSCs were exposed to iAs at different durations to track cellular aging and study long-term genetic stability. iAs exposures (48 h) resulted in micronuclei induction. hMSCs were also exposed to iAs for 6 days to determine if hMSCs would become more susceptible to chromosomal damage following exposure to the model genotoxicant, mitomycin C (MMC). The culture duration and iAs exposure did not alter MMC potency, indicating that the hMSC susceptibility to chromosomal damage remained unchanged. We also used gene expression analysis to investigate the molecular impacts of iAs on hMSCs over the course of short (3 days total) and long (30 days total) experiments. Both iAs exposures activated biomarkers associated with oxidative stress, but not biomarkers for direct DNA damage, providing support for an indirect mode of action for iAs genotoxicity. Overall, this study establishes the utility of hMSCs as a new model for toxicity screening and provides mechanistic information underlying iAs toxicity.