Development of Assays for Neurotoxicity Using Human iPSC-derived Neurons

Development of Assays for Neurotoxicity Using Human iPSC-derived Neurons

Development of Assays for Neurotoxicity Using Human iPSC-derived Neurons

  • Date: September 20, 2016
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Human cell types differentiated from induced pluripotent stem cells (iPSC) offer a unique source of cellular material for toxicity screening. Several examples have been presented on iPSC-derived cardiomyocytes and hepatocytes use in safety toxicology studies. Equally important is comparative neurotoxicity assessment in neuronal cell types for safety toxicology and uncovering molecular mechanisms underlying excitotoxic cell death pathways. Advances in iPSC technology provide access to previously unattainable cell types from the human brain opening new opportunities to address the limitations of rodent primary cells and immortalized cell lines. Here, we present neurotoxic effects of the excitatory neurotransmitter glutamate and related compounds across a panel of iPSC-derived neuronal cell types, including cortical GABAergic and glutamatergic neurons, and midbrain dopaminergic neurons. Cytotoxicity of a broad-spectrum kinase inhibitor, staurosporine (STS), was also evaluated. Under the various conditions tested, we observed differential responses for glutamatergic compounds versus STS, suggesting the toxicity responses were due to excitotoxic effects through neuronal synaptic receptors. Importantly, toxicity induced by glutamate could be reversed with antagonists of the AMPA and NMDA receptors, DNQX and AP5, respectively. Overall, these iPSC-derived neurons exhibit functional glutamate pathways that respond appropriately to known agonists and antagonists, thus providing biologically relevant models for identifying emerging targets for excitotoxicity research. Together with the developmental and environmental toxicity studies, these data establish human iPSC-derived neurons as a reliable and predictive tool for use in neurotoxicity studies.

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