Human Pluripotent Stem Cells as Tools for Predicting Developmental Neural Toxicity of Chemicals: Strategies, Applications, and Challenges

The human central nervous system (CNS) is very sensitive to perturbations, since it performs sophisticated biological processes and requires cooperation from multiple neural cell types. Subtle interference from exogenous chemicals, such as environmental pollutants, industrial chemicals, drug components, food additives, and cosmetic constituents, may initiate severe developmental neural toxicity (DNT). Human pluripotent stem cell (hPSC)-based neural differentiation assays provide effective and promising tools to help evaluate potential DNT caused by those toxicants. In fact, the specification of neural lineages in vitro recapitulates critical CNS developmental processes, such as patterning, differentiation, neurite outgrowth, synaptogenesis, and myelination. Hence, the established protocols to generate a repertoire of neural derivatives from hPSCs greatly benefit the in vitro evaluation of DNT. In this review, we first dissect the various differentiation protocols inducing neural cells from hPSCs, with an emphasis on the signaling pathways and endpoint markers defining each differentiation stage. We then highlight the studies with hPSC-based protocols predicting developmental neural toxicants, and discuss remaining challenges. We hope this review can provide insights for the further progress of DNT studies.