Comparison of Human Induced Pluripotent Stem Cell-Derived Neurons and Rat Primary Cortical Neurons as In Vitro Models of Neurite Outgrowth

High-throughput, high-content imaging (HCI) assays for the key cellular events of neurodevelopment have been proposed to rapidly evaluate chemicals for developmental neurotoxicity. Thus, in vitro assays using neural cell cultures are being developed for key neurodevelopmental events, including proliferation, neural differentiation, migration, synaptogenesis, and neurite outgrowth. The advent of human induced pluripotent stem cell (iPSC)-derived neurons provides a novel model system. Human iPSC-derived neurons demonstrate the morphology and physiology of their in situ counterparts and have been commercialized and made available in large numbers, facilitating their use in chemical testing. The present study evaluated the neuronal characteristics of commercially available, cryopreserved human iPSC-derived neurons (iCell® neurons). Immunocytochemistry revealed a relatively pure population of neurons that extended both putative axons and dendrites. The cells developed neurites rapidly and consistently as quantified using automated HCI. Exposure to a training set of eight chemicals previously demonstrated to affect neurite outgrowth in rodent and/or human neurons resulted in concentration-dependent decreases in neurite outgrowth in human iCell neurons, although the response to chemicals was different from the response observed in rat cortical neurons. Lead and U0126 had no effect in rat cortical neurons but decreased neurite outgrowth in human neurons. In contrast, etoposide decreased both neurite outgrowth and viability in rat primary cortical cultures, but was much less potent in human iPSC-derived neurons. Together, these data demonstrate that commercially available human iPSC-derived neurons are amenable for use in medium- to high-throughput assays of neurite outgrowth using HCI. Though limited, the data indicate that human and rodent neurons can respond differently to chemical insult, and suggest that in vitro toxicity testing should include the use of human-derived cells.