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Phenotypic Screening of human iPSC-Derived Neurons identifies Thienopyridone as a Neuritogenic Small Molecule

ABSTRACT: Human induced pluripotent stem cell (iPSC)-derived neurons provide a platform for modeling a wide range of brain disorders. Among disease-relevant cellular phenotypes, impaired neurite outgrowth has emerged as a robust and quantifiable indicator that reflects core aspects of neurodevelopmental and neurodegenerative disease pathophysiology. In this study, we performed a high-throughput phenotypic chemical screen of over 21,000 small molecules to identify compounds that enhance neurite outgrowth in iPSC-derived cortical neurons.By iterative validation using disease-specific and control iPSC-derived neuronal lines, we identified three bioactive compounds that were sharing a common indazole scaffold. Two hit compounds were further validated in a human neural organoid model, where they proliferated neural stem cells by reproducing the neurite-promoting effect. Transcriptomic profiling revealed activation of signaling pathways associated with neurotrophic stimulation. These findings identified a novel scaffold for a neurogenic compound, suggesting the potential of this compound as a therapeutic strategy for brain disorders and for promoting neural regeneration.

ORGANISM(S): Homo sapiens

PROVIDER: GSE308370 | GEO | 2026/03/19

REPOSITORIES: GEO

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Project description:Dysregulated neurite outgrowth and synapse formation underlie many psychiatric disorders. Wolfram syndrome (WS) mainly caused by WFS1 deficiency is a monogenic genetic disease manifested by severe psychiatric disorders. Due to athe lack of proper human disease models, the underlying mechanism is poorly understood. Particularly, whether and how WFS1 deficiency affects synapse formation remain elusive. By mirroring the complexity of human brain development with cerebral organoids derived from human embryonic stem cells (hESCs) harboring WFS1 loss of function (LOF), we found that WFS1-deficient cerebral organoids not only recapitulated the neuronal loss phenotype in WS patients, but also exhibited significantly impaired synapse formation associated with reduced astrocytes, suggesting a defective structural basis for psychiatric disorders elicited by WFS1 deficiency. To further unravel the complexity of interplay between neurons and astrocytes, each neural cell type was respectively differentiated from hESCs harboring WFS1 LOF. WFS1 deficiency in neurons autonomously delayed neuronal differentiation with altered expressions of genes associated with psychiatric disorders, and impaired neurite outgrowth and reduced synapse formation associated with elevated cytosolic calcium. Interestingly, WFS1 deficiency in astrocytes decreased the expression of glutamate transporter EAAT2 and compromised glutamate uptake, causing reduced neurite outgrowth with increased cytosolic calcium when co-cultured with wildtype (WT) neurons, highlighting pathogenic role of WFS1-deficient astrocytes. Importantly, restoring EAAT2 expression in astrocytes by riluzole treatment significantly alleviated reduced neurite outgrowth phenotype in WT neurons co-cultured with WFS1-deficient astrocytes. Altogether, our study provides novel insights into how WFS1 deficiency affects neurite outgrowth and synapse formation, potentially contributing to predisposition of psychiatric disorders, and offers a potential strategy of therapy.

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Phenotypic Screening of human iPSC-Derived Neurons identifies Thienopyridone as a Neuritogenic Small Molecule

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