DEVELOPING HPSC-DERIVED IN VITRO MODELS AS ALTERNATIVES FOR NEURODEVELOPMENTAL TOXICITY SCREENING

Animal models are the traditional gold standard for studying neurodevelopment. However, there is a need for more reliable, reproducible, and cost-effective alternatives. Human pluripotent stem cells (hPSCs) are a transformative tool for replicating human neurodevelopment in vitro.
We established two complementary in vitro models to evaluate neurodevelopmental mechanisms and drug toxicity. The first platform uses a monolayer system optimized for high-throughput screening. Using a robust differentiation protocol, we generated hPSC-derived neural epithelial progenitors (hNEPs), neural progenitor cells (hNPCs), and mature ventral forebrain neurons. To validate the model's sensitivity, these stages were exposed to a panel of well-characterized neurotoxicants, including specific drugs, heavy metals, and pesticides with known adverse effects. Our results demonstrated dose-dependent toxicological responses, allowing us to determine the IC₅₀ for each compound across different developmental windows.
To address the complexity of neural connectivity, we developed a brain-on-chip model that allows the independent differentiation of hPSCs into region-specific neurons within isolated chambers. Our results demonstrated that this device enables these distinct populations to interact via synaptic connections, establishing a mature neuronal network that recapitulates the basal ganglia circuitry. Functional analyses revealed that cortical innervation significantly enhances the maturation and functionality of striatal neurons. This system also offers a versatile tool for disease modeling. By using disease-derived hPSC, we can mimic the human developmental affections occurring in some neurodegenerative diseases.
In conclusion, these models provide a robust framework to study neurodevelopment, offering a scalable, human-relevant alternative to animal models for drug screening and neurotoxicity testing.