Abstract The human central nervous system CNS is very vulnerable Free Essay Example

Abstract: The human central nervous system (CNS) is very vulnerable to perturbations, since it performs sophisticated biological processes and requires cooperation from multiple neural cell types. Subtle interference from exogenous chemicals may initiate severe developmental neural toxicity (DNT). Human pluripotent stem cells (hPSCs)-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, myelination, etc.

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.

Keywords: Developmental neural toxicity (DNT); human pluripotent stem cells (hPSCs); neural differentiation; neurons; astrocytes; oligodendrocytes.

1. Introduction

Developmental neural disorders, such as autism, attention-deficit hyperactivity disorder, dyslexia, mental retardation, and other impairments of the nervous system, affect millions of children worldwide, and may cause lifelong disabilities (Grandjean and Landrigan, 2014; Landrigan et al., 2012). Although some of the developmental neural disorders may have a genetic origin, accumulating evidence suggests a significant contribution of industrial chemicals on the onset and/or progression of these medical conditions. For instance, environmental pollutants including polychlorinated biphenyls (PCBs), polybrominated diphenyl ethers (BDEs), dioxins and phthalates, have been proved to cause 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 applications of these chemicals have been strictly limited or even abandoned. Nevertheless, these recognized developmental neural toxicants may just be the tip of the iceberg.

Several animal models based on rats, mice, zebrafish, rabbits, etc., have been used to represent humans for in vivo screening of toxicants causing developmental neural disorders. Though animal assays have played important roles in toxicology and provided abundant information on potential developmental neural toxicants, their ethical issues and innate drawbacks, such as 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 primary cells derived from individual donors, represent suitable alternatives to live animal experiments, to assess DNT (Moors et al., 2009; Schreiber et al., 2010). However, the availability of human primary cells is limited, making large-scale chemical screens impractical (Hou et al., 2013).

Pluripotent stem cells (PSCs), including 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, providing excellent alternative methods 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 test (EST). It consisted in cytotoxicity analyses of proliferating and differentiating mouse ESCs, as well as 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 goal of establishing a battery of developmental toxicity tests in vitro with DNT as one of the major tasks (Rovida et al., 2014). Nowadays, the advances in our understanding of the molecular mechanisms of neural specification in vivo and in vitro, advocate for the use of hPSCs for developing and implementing accurate, high-performance and high-throughput methods to screen developmental neural toxicants. In this review, we analyze the various neural differentiation protocols from hPSCs, with a focus on their signaling pathways and endpoint markers defining each differentiation stage, and highlight their applications in developmental neural toxicants’ screenings, without forgetting the challenges we must overcome to allow these assays to become the gold standards for DNT evaluations.

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