Life Med: Liu Yan of Nanjing Medical University uses brain organoids to simulate high cholesterol exposure leading to neurodevelopmental abnormalities

Due to unhealthy diet and living habits, obesity has become a serious social health problem
.
Maternal obesity accompanied by increased cholesterol levels before or during pregnancy has been reported to affect brain development in offspring, which in turn may lead to neurodevelopmental or neuropsychiatric disorders
.
Cohort studies have also shown an increased
risk of autism, depression and schizophrenia in offspring of obese mothers.
However, the relationship between maternal obesity and neurodevelopmental defects in offspring remains unclear
.

Liu Yan's research group at the School of Pharmacy of Nanjing Medical University published a research paper
entitled Modeling maternal cholesterol exposure reveals a reduction of neural progenitor proliferation using human cerebral organoids online in the journal Life Medicine 。 In this study, human brain organoids were used as a research model, and the exogenous addition of high cholesterol simulated the development environment in which maternal obesity caused by fetal exposure to high cholesterol was simulated, revealing that the developmental environment of high cholesterol can lead to early differentiation of neural progenitor cells
.

The researchers added extra cholesterol to human brain organoids to mimic the high cholesterol environment
during pregnancy.
In brain organoids to which cholesterol is added, the endosomes of the neural progenitor cell region swell, and their number increases to some extent
.
Suggests that neuroprogenitor cells
are affected in cholesterol-treated brain organoids.

The study found that the proliferation of neural progenitor cells in brain organoids added to cholesterol decreased, but there was no increase in indicators related to aging and apoptosis, indicating that the decrease in neural progenitor cell proliferation was not caused by
aging and apoptosis.
Further analysis revealed that neural progenitor cells in cholesterol-added brain organoids advanced into neurons
.

A maternal environment with high cholesterol may increase the risk of neurodevelopmental disorders in offspring, including intellectual disability, autism, and other neuropsychiatric disorders
.
The researchers compared the set of differentially expressed genes in cholesterol-treated brain organs and controls associated with autism, schizophrenia and intellectual disability
.
The results showed that these differential genes had the highest degree of overlap with the
set of genes associated with autism.
In addition, the researchers compared this single-cell sequencing data with published single-cell sequencing data from brain organs of disease origin and found that the transcription profiles of cholesterol-treated brain organs were similar to those of brain organs from patients with autism
.
These results suggest that cholesterol-treated brain organs are somewhat similar
to autism.

By exogenously adding cholesterol to brain organ culture systems, this study found that maternal high cholesterol exposure can lead to endosome enlargement and aggregation within neural progenitor cell regions, decreased neural progenitor cell proliferation, and premature neural differentiation
.
This work provides a dynamic human-derived brain model
for studying potential maternal toxic exposures in the first trimester.

Professor Liu Yan and Dr.
Han Xiao, School of Pharmacy, Nanjing Medical University, are the co-corresponding authors of this paper; Fan Pan, a 2022 master student in the School of Pharmacy, is the first author of this paper (now a doctoral student at the School of Basic Medicine of Nanjing Medical University).

This research was supported
by the National Key R&D Program, the Strategic Leading Science and Technology Project of the Chinese Academy of Sciences, and the National Natural Science Foundation of China.

Original link:

Pan Fan, et al.
Modeling maternal cholesterol exposure reveals a reduction of neural progenitor proliferation using human cerebral organoids.
Life Medicine, https://doi.
org/10.
1093/lifemedi/lnac034

About the author

Liu Yan Nanjing Medical University

Ph.
D.
in
Human Anatomy and Histology and Embryology, Shanghai Medical College, Fudan University.
From 2008 to 2013, he was engaged in stem cell and neural regeneration research
at the Waisman Center at the University of Wisconsin.
Since September 2013, he has been working as a researcher
at the School of Pharmacy, Nanjing Medical University.
It has been supported
by the National Outstanding Youth Fund, the key research and development project of the Ministry of Science and Technology, and the strategic leading science and technology special project of the Chinese Academy of Sciences.
He has long been committed to the research and development of neural lineage directed differentiation of human pluripotent stem cells and human brain organoid disease models, focusing on the research of nerve regeneration and neural diseases.
The results were published as corresponding authors or first authors in journals such as Nature Biotechnology, Nature communications, Molecular Psychiatry, Journal of Clinical Investigation and EMBO Molecular Medicine
.