Human pluripotent stem cell-derived 2D neural tissue samples for predictive neurotoxicity screening
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ABSTRACT:
PROVIDER: PRJNA523269 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR8593640.fastq.gz | Fastqsanger.gz | |||
| SRR8593650.fastq.gz | Fastqsanger.gz | |||
| SRR8593660.fastq.gz | Fastqsanger.gz | |||
| SRR8593670.fastq.gz | Fastqsanger.gz | |||
| SRR8593680.fastq.gz | Fastqsanger.gz |
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Project description:There is a growing need for fast and accurate methods for testing developmental neurotoxicity across industrial, pharmaceutical, and environmental chemical exposures. Current approaches, such as in vivo animal studies, and assays of animal and human primary cell cultures, suffer from challenges related to time, cost, and applicability to human physiology. Prior research demonstrated success employing machine learning to predict developmental neurotoxicity using gene expression data collected from complex human 3D tissue models exposed to various compounds, but the complexity of 3D tissue models require extensive expertise and effort to employ. While a 3D tissue model is more physiologically accurate, by focusing only on the goal of constructing an assay of developmental neurotoxicity, we propose that a simpler 2D tissue model may prove sufficient. We thus compared the accuracy of predictive models trained on data from a 2D tissue model with those trained on prior dataset from a more complex 3D tissue model, and found the accuracy of the 2D model to be substantially better than the 3D model. Furthermore, we found that the 2D tissue model is more robust and consistent under stringent gene set selection, whereas the 3D tissue model suffers substantial degradation of accuracy. While both approaches have advantages and disadvantages, we propose that our described 2D tissue model has the potential to serve as a valuable tool for decision makers when prioritizing neurotoxicity screening.
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Project description:Human pluripotent stem cell-based in vitro models that reflect human physiology have the potential to reduce the number of drug failures in clinical trials, and offer a cost effective approach for assessing chemical safety. Here, human embryonic stem (ES) cell-derived neural progenitor cells, endothelial cells, mesenchymal stem cells, and microglia/macrophage precursors were combined on chemically-defined poly(ethylene glycol) (PEG) hydrogels and cultured in serum-free media to model cellular interactions of the developing brain. The precursors self-assembled into 3-dimensional (3D) neural constructs with cortically organized neuronal and glial cells, interconnected vascular networks, and ramified microglia. Replicate constructs were highly reproducible by RNA sequencing (Spearman’s correlation coefficients, ρ ≥ 0.97) and robustly expressed neurogenesis, vasculature development, and microglia genes. Finally, linear support vector machines were used to construct a predictive model from RNA sequencing data for 240 neural constructs treated with 60 toxic and non-toxic chemicals, which then correctly classified 9/10 blinded compounds.
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Project description:Acute exposure to acrylamide (ACR), a type-2 alkene, may lead to a ataxia, skeletal muscles weakness and numbness of the extremities in exposed human and laboratory animals. Recently, a zebrafish model for ACR neurotoxicity mimicking most of the pathophysiological processes described in mammalian models, was generated in 8 days post-fertilization larvae. In order to better understand the predictive value of the zebrafish larvae model of acute ACR neurotoxicity, in the present manuscript the ACR acute neurotoxicity has been characterized in the brain of adult zebrafish, and the results compared with those obtained with the whole-larvae. Although qualitative and quantitative analysis of the data shows important differences in the ACR effects between the adult brain and the whole-larvae, the overall effects of ACR in adult zebrafish, including a significant decrease in locomotor activity, altered expression of transcriptional markers of proteins involved in synaptic vesicle cycle, presence of ACR-adducts on cysteine residues of some synaptic proteins, and changes in the profile of some neurotransmitter systems, are similar to those described in the larvae. Thus, these results support the suitability of the zebrafish ACR acute neurotoxicity recently developed in larvae for screening of molecules with therapeutic value to treat this toxic neuropathy.
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