Abstract: The human central nervous system (CNS) may be very weak to perturbations, because it performs sophisticated organic processes and requires cooperation from multiple neural cell sorts. Subtle interference from exogenous chemical compounds may initiate extreme developmental neural toxicity (DNT). Human pluripotent stem cells (hPSCs)-based neural differentiation assays provide effective and promising tools to help consider potential DNT caused by those toxicants. In truth, the specification of neural lineages in vitro recapitulates critical CNS developmental processes, such as patterning, differentiation, neurite outgrowth, synaptogenesis, myelination, etc.
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Hence, the established protocols to generate a repertoire of neural derivatives from hPSCs tremendously profit the in vitro evaluation of DNT. In this evaluate, we first dissect the assorted differentiation protocols inducing neural cells from hPSCs, with an emphasis on the signaling pathways and endpoint markers defining every differentiation stage. We then highlight the research with hPSC-based protocols predicting developmental neural toxicants, and focus on remaining challenges. We hope this evaluate can present insights for the further progress of DNT research.
Keywords: Developmental neural toxicity (DNT); human pluripotent stem cells (hPSCs); neural differentiation; neurons; astrocytes; oligodendrocytes.
Developmental neural disorders, corresponding to autism, attention-deficit hyperactivity disorder, dyslexia, psychological retardation, and different impairments of the nervous system, have an effect on hundreds of thousands of children worldwide, and may cause lifelong disabilities (Grandjean and Landrigan, 2014; Landrigan et al., 2012). Although a variety of the developmental neural disorders could have a genetic origin, accumulating evidence suggests a big contribution of industrial chemical substances on the onset and/or development of these medical situations. For occasion, environmental pollution together with polychlorinated biphenyls (PCBs), polybrominated diphenyl ethers (BDEs), dioxins and phthalates, have been proved to trigger developmental neural toxicity (DNT) in in vitro and in vivo studies (Colborn et al.
, 1993; Costa and Giordano, 2007; Miodovnik et al., 2014). Because of that, many functions of these chemicals have been strictly restricted and even deserted. Nevertheless, these acknowledged developmental neural toxicants may be the tip of the iceberg.
Several animal fashions primarily based on rats, mice, zebrafish, rabbits, and so on., have been used to symbolize humans for in vivo screening of toxicants inflicting developmental neural problems. Though animal assays have played important roles in toxicology and provided ample info on potential developmental neural toxicants, their moral points and innate drawbacks, similar to interspecies variations, and being labor intensive and time consuming, make them defective (Faiola et al., 2015; Hartung, 2009; Hou et al., 2013). In vitro assays with human main cells derived from individual donors, represent suitable options to live animal experiments, to evaluate DNT (Moors et al., 2009; Schreiber et al., 2010). However, the supply of human major cells is restricted, making large-scale chemical screens impractical (Hou et al., 2013).
Pluripotent stem cells (PSCs), together with mouse/human embryonic stem cells (ESCs) and mouse/human induced pluripotent stem cells (iPSCs), have the capacity to proliferate extensively and differentiate into multi-lineages, offering wonderful various strategies for DNT assays in vitro (Faiola et al., 2015; Yao et al., 2016). The very first well-known system applying PSCs for developmental toxicity assays was the embryonic stem cell check (EST). It consisted in cytotoxicity analyses of proliferating and differentiating mouse ESCs, in addition to control embryonic fibroblasts, to predict potential embryo-toxicants (Genschow et al., 2004; Scholz et al., 1997). Inspired by the EST assay, the Embryonic Stem cell-based Novel Alternative Testing Strategies (ESNATS) project was launched in 2008, with the aim of establishing a battery of developmental toxicity exams in vitro with DNT as one of many major duties (Rovida et al., 2014). Nowadays, the advances in our understanding of the molecular mechanisms of neural specification in vivo and in vitro, advocate for using hPSCs for developing and implementing accurate, high-performance and high-throughput strategies to display developmental neural toxicants. In this evaluation, we analyze the varied neural differentiation protocols from hPSCs, with a give attention to their signaling pathways and endpoint markers defining each differentiation stage, and spotlight their functions in developmental neural toxicants’ screenings, without forgetting the challenges we must overcome to allow these assays to become the gold requirements for DNT evaluations.