Altered extracellular matrix structure and elevated stiffness in a brain organoid model for disease

The viscoelastic properties of tissues influence their morphology and cellular behavior, yet little is known about changes in these properties during brain malformations. Lissencephaly, a severe cortical malformation caused by LIS1 mutations, results in a smooth cortex. Here, we show that human-derived brain organoids with LIS1 mutation exhibit increased stiffness compared to controls at multiple developmental stages. This stiffening correlates with abnormal extracellular matrix (ECM) expression and organization, as well as elevated water content, measured by diffusion-weighted MRI. Short-term MMP9 treatment reduces both stiffness and water diffusion levels to control values. Additionally, a computational microstructure mechanical model predicts mechanical changes based on ECM organization. These findings suggest that LIS1 plays a critical role in ECM regulation during brain development and that its mutation leads to significant viscoelastic alterations.

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Publication Details

Journal
Nature Communications
Published
2025-05-01
DOI
https://doi.org/10.1038/s41467-025-59252-w
Citations
10
Primary Topic
Cellular Mechanics and Interactions
Type
article
Field-Weighted Citation Impact
11.51

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Altered extracellular matrix structure and elevated stiffness in a brain organoid model for disease

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Altered extracellular matrix structure and elevated stiffness in a brain organoid model for disease

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article en
10 citations

Abstract

The viscoelastic properties of tissues influence their morphology and cellular behavior, yet little is known about changes in these properties during brain malformations. Lissencephaly, a severe cortical malformation caused by LIS1 mutations, results in a smooth cortex. Here, we show that human-derived brain organoids with LIS1 mutation exhibit increased stiffness compared to controls at multiple developmental stages. This stiffening correlates with abnormal extracellular matrix (ECM) expression and organization, as well as elevated water content, measured by diffusion-weighted MRI. Short-term MMP9 treatment reduces both stiffness and water diffusion levels to control values. Additionally, a computational microstructure mechanical model predicts mechanical changes based on ECM organization. These findings suggest that LIS1 plays a critical role in ECM regulation during brain development and that its mutation leads to significant viscoelastic alterations.

Nature CommunicationsVol. 16(1)
Hebrew University of Jerusalem (IL), Jerusalem Institute for Israel Studies (IL), Weizmann Institute of Science (IL), Syracuse University (US)
Impact Fund, United States-Israel Binational Science Foundation, Israel Science Foundation
Openalex Percentile: Top 1%
Cellular Mechanics and Interactions
11.51
DOIOpen Access PDFOpenAlex
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