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

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Organoid Extracellular matrix Disease Matrix (chemical analysis) Extracellular Cell biology Biology Neuroscience Computational biology Medicine Pathology Chemistry Chromatography

M. Zur , Bidisha Bhattacharya , Inna Solomonov , Sivan Ben Dror , Alon Savidor , Yishai Levin , Amir Prior , Tamar Sapir , Talia Harris , Tsviya Olender , Rita Schmidt , JM Schwarz , Órit Kollet , Amnon Buxboim , Orly Reiner ·

YOU? · · 2025 · Open Access · · DOI: https://doi.org/10.1038/s41467-025-59252-w · OA: W4409995020

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.