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Updated: Apr 26, 2026
Generation of Standardized and Reproducible Forebrain-type Cerebral Organoids from Human Induced Pluripotent Stem Cells
Published on: January 23, 2018
Multiomics analysis identifies VPA-induced changes in neural progenitor cells, ventricular-like regions, and cellular
Zeynep Yentür1,2,3,4,5, Lizia Branco5, Kseniia Sarieva2,3,4
1The Heidelberg Academy of Sciences and Humanities, Heidelberg, Germany.
Insights
Prenatal exposure to valproate (VPA) disrupts extracellular matrix and cell signaling in developing human brain organoids. This research models how VPA impacts neurodevelopment, offering insights into autism spectrum disorder and congenital malformations.
Area of Science:
- Neuroscience
- Developmental Biology
- Pharmacology
Background:
- Pharmaceutical agents can cross the fetal barrier and impact the developing brain.
- Prenatal exposure to antiepileptic drugs like valproate (VPA) is linked to neurodevelopmental disorders, including autism spectrum disorder.
- VPA affects signaling pathways, such as the Wnt pathway, in animal models and neural organoids.
Purpose of the Study:
- To investigate the effects of VPA on human dorsal forebrain organoids at tissue, cellular, and molecular levels.
- To explore VPA's impact on extracellular processes and microenvironment sensing during early brain development.
- To establish VPA-treated dorsal forebrain organoids as a model for studying neurodevelopmental disorders.
Main Methods:
- Exposure of dorsal forebrain organoids to VPA for 30 days.
- Analysis of tissue, cellular, and molecular changes using transcriptomics, single-cell RNA sequencing, and proteomics.
- Examination of disruptions in ventricular-like regions, cell-cell, and cell-matrix interactions.
Main Results:
- VPA treatment disrupted ventricular-like regions, indicating impaired cell-cell and cell-matrix interactions.
- Transcriptomics revealed altered expression of extracellular matrix (ECM) genes.
- Single-cell RNA sequencing identified affected genes in microenvironment sensing, including cellular mechanosensing and the Hippo-YAP/TAZ pathway.
- Proteomics confirmed VPA's disruption of ECM protein secretion, altering the organoid microenvironment.
Conclusions:
- VPA alters the extracellular microenvironment in developing human dorsal forebrain organoids.
- Disruptions in extracellular processes and microenvironment sensing may contribute to VPA-induced neurodevelopmental defects.
- VPA-treated dorsal forebrain organoids provide a valuable model for investigating the role of extracellular processes in brain development and neurodevelopmental disorders.
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. In animal models and neural organoids, VPA has been shown to alter signaling pathways, such as Wnt pathway, providing insights into VPA-induced neurodevelopmental defects. Here, we exposed dorsal forebrain organoids to VPA for 30 days and examined effects at the tissue, cellular, and molecular level. VPA treatment disrupted ventricular-like regions, indicating defects in cell-cell and cell-matrix interactions. Transcriptomics analysis confirmed altered expression of extracellular matrix (ECM) genes and single cell RNA sequencing analysis identified genes involved in 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 ECM proteins. Altogether, our study suggests that 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.
