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Multiomic analysis identifies VPA induced changes in neural progenitor cells, ventricular-like regions and cellular microenvironment in dorsal forebrain organoids

ABSTRACT: Pharmaceutical agents, such as antiepileptic medications, can cross fetal barriers and affect the developing brain. Prenatal exposure to the antiepileptic drug valproate (VPA) is associated with an increased risk of neurodevelopmental disorders, including congenital malformations and autism spectrum disorder. VPA-treated animal models and neural organoids proposed defects in intracellular mechanisms such as Wnt signaling underlying VPA-induced neurodevelopmental adversities. However, the influence of extracellular mechanisms on these defects remains unexplored. Here, we showed that VPA treatment disrupted ventricular-like regions, suggesting defects in cell-cell and cell-matrix interactions. Transcriptomics analyses confirmed the disruption of ECM secretion as well as intracellular processes related to microenvironment sensing, such as cellular mechanosensing and Hippo-YAP/TAZ signaling pathway. Finally, proteomics analysis corroborated that VPA alters the microenvironment of the human dorsal forebrain organoids by disrupting the secretion of extracellular matrix (ECM) proteins. Altogether, our study suggests VPA-treated dorsal forebrain organoids serve as a model to investigate the role of extracellular processes in brain development and to understand how their disruptions might contribute to neurodevelopmental disorders.

INSTRUMENT(S): Orbitrap Fusion

ORGANISM(S): Homo Sapiens (ncbitaxon:9606)

SUBMITTER: Mohamed Ali Jarboui

PROVIDER: MSV000097991 | MassIVE | Mon May 26 00:06:00 BST 2025

SECONDARY ACCESSION(S): PXD064286

REPOSITORIES: MassIVE

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