Modeling maternal cholesterol exposure reveals a reduction of neural progenitor proliferation using human cerebral organoids

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.