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

Maayan Karlinski Zur, Bidisha Bhattacharya, Inna Solomonov, Sivan Dror, Alon Savidor, Yishai Levin, Amir Prior, Tamar Sapir, Talia Harris, Tsviya Olender, Rita Schmidt, J. M. Schwarz, Irit Sagi (), Amnon Buxboim () and Orly Reiner ()
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Maayan Karlinski Zur: Weizmann Institute of Science
Bidisha Bhattacharya: Weizmann Institute of Science
Inna Solomonov: Weizmann Institute of Science
Sivan Dror: The Hebrew University of Jerusalem, The Edmond J. Safra Campus
Alon Savidor: Weizmann Institute of Science
Yishai Levin: Weizmann Institute of Science
Amir Prior: Weizmann Institute of Science
Tamar Sapir: Weizmann Institute of Science
Talia Harris: Weizmann Institute of Science
Tsviya Olender: Weizmann Institute of Science
Rita Schmidt: Weizmann Institute of Science
J. M. Schwarz: Syracuse University
Irit Sagi: Weizmann Institute of Science
Amnon Buxboim: The Hebrew University of Jerusalem, The Edmond J. Safra Campus
Orly Reiner: Weizmann Institute of Science

Nature Communications, 2025, vol. 16, issue 1, 1-16

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-59252-w

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