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Updated: May 30, 2025
Generation of iPSC-derived Human Brain Organoids to Model Early Neurodevelopmental Disorders
Published on: April 14, 2017
Modeling maternal cholesterol exposure reveals a reduction of neural progenitor proliferation using human cerebral
Pan Fan1, Yuanhao Wang1, Kaiqin Lu1
1Institute for Stem Cell and Neural Regeneration, State Key Laboratory of Reproductive Medicine, School of Pharmacy, Nanjing Medical University, Nanjing 211166, China.
Insights
Maternal high cholesterol exposure may increase autism risk in offspring. This study used brain organoids to show cholesterol impairs neural progenitor proliferation, a potential indicator for prenatal diagnosis.
Area of Science:
- Neuroscience
- Developmental Biology
- Stem Cell Research
Background:
- Maternal obesity is linked to offspring neurodevelopmental disorders, including autism spectrum disorders (ASDs).
- The specific role of high cholesterol exposure and its mechanisms in causing brain developmental defects remain unclear.
Purpose of the Study:
- To investigate the direct impact of high cholesterol exposure on human brain development.
- To elucidate the underlying mechanisms by which cholesterol may contribute to neurodevelopmental risks.
Main Methods:
- Utilized human pluripotent stem cell (hPSC)-derived cerebral organoids as a model system.
- Exogenously added cholesterol to the culture medium to create a high-cholesterol exposure model.
- Analyzed organoid development using single-cell sequencing and compared transcriptome data.
Main Results:
- Cholesterol treatment led to enlarged endosomes, reduced neural progenitor proliferation, and premature neural differentiation in brain organoids.
- Single-cell sequencing data showed a strong correlation with existing autism spectrum disorder (ASD) transcriptome data.
- Observed reduction in neural progenitor proliferation may serve as a key indicator.
Conclusions:
- High cholesterol exposure during critical developmental periods can negatively impact brain development.
- Reduced neural progenitor proliferation is a potential mechanism linking maternal high cholesterol to increased ASD risk in offspring.
- This model offers a valuable tool for studying maternal environmental exposures and prenatal diagnosis.
Abstract:
Maternal obesity raises the risk of high-cholesterol exposure for their offspring. Studies in cohorts and animal models report that maternal obesity could increase the risk of neurodevelopmental disorders in offspring including intellectual disabilities and autism spectrum disorders (ASDs). However, whether exposure to high cholesterol is responsible for brain developmental defects, as well as its underlying mechanism, is still unclear. Here, we constructed a cholesterol exposure model utilizing human pluripotent stem cell (hPSC)-derived cerebral organoids by exogenously adding cholesterol into the culture system. We observed enlargement of endosomes, decreased neural progenitor proliferation, and premature neural differentiation in brain organoids with the treatment of cholesterol. Moreover, in comparison with published transcriptome data, we found that our single-cell sequencing results showed a high correlation with ASD, indicating that high cholesterol during maternal might mediate the increased risk of ASD in the offspring. Our results reveal a reduction of neural progenitor proliferation in a cholesterol exposure model, which might be a promising indicator for prenatal diagnosis and offer a dynamic human model for maternal environment exposure.
