Abstract: Over the last few years, we have seen an increase in the use of organotypic cell cultures, and specifically models of the brain. Human in-vitro models of brain neurophysiology are needed to investigate molecular and cellular mechanisms associated with neurological disorders and neurotoxicity. We have developed a reproducible iPSC-derived human 3D brain model (also called BrainSpheres), comprised of differentiated mature neurons and glial cells (astrocytes and oligodendrocytes) that reproduce neuronal-glial interactions and connectivity. The model has previously shown to be reproducible and recapitulates several features in neurodevelopment. The model matures over eight weeks and shows the critical elements of neuronal function: synaptogenesis, neuron-to-neuron (e.g. spontaneous electric field potentials) and neuronal-glial interactions (e.g. myelination), that mimic the microenvironment of the central nervous system, rarely seen in vitro so far. The model shows 40% overall myelination after 8 weeks of differentiation. Thus, the BrainSpheres provides a suitable and reliable model to investigate neuron-neuroglia function in neurotoxicology or other pathogenic mechanisms. Our model has been used for many applications, such as inflammation studies, neurotoxicity, cancer research, virus infectious diseases, Parkinson’s diseases, and others. For example, BrainSpheres were used to study rotenone as a possible DNToxicant. Results indicate, that the rotenone toxic potency varies depending on the differentiation status of the cells, showing early stages of differentiation more sensitivity to this compound. Omics analysis shows some modified key pathways for brain development, indicating rontenone as a developmental neurotoxicant. In this presentation, we summarize the model and its different applications.
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