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

Maayan Karlinski Zur; Bidisha Bhattacharya; Inna Solomonov; Sivan Ben Dror; Alon Savidor; Yishai Levin; Amir Prior; Tamar Sapir; Talia Harris; Tsviya Olender; Rita Schmidt; J. M. Schwarz; Irit Sagi; Amnon Buxboim; Orly Reiner

doi:10.1038/s41467-025-59252-w

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

Maayan Karlinski Zur, Bidisha Bhattacharya, Inna Solomonov, Sivan Ben Dror, Alon Savidor, Yishai Levin, Amir Prior, Tamar Sapir, Talia Harris, Tsviya Olender, Rita Schmidt, J. M. Schwarz, Irit Sagi^*, Amnon Buxboim^*, Orly Reiner^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Article number	4094
Journal	Nature Communications
Volume	16
DOIs	https://doi.org/10.1038/s41467-025-59252-w
Publication status	Published - 1 May 2025

Funding

We express our gratitude for the help of Arpan Parichha, Alfredo Isaac Ponce Arias, Mahesh Gandikota, and Tao Zhang. Orly Reiner is an incumbent of the Berstein-Mason professorial chair of Neurochemistry and the Head of the M. Judith Ruth Institute for Preclinical Brain Research. I.S. is an incumbent of the Maurizio Pontecorvo Professorial Chair. Our research has been supported by research grants from Ethel Lena Levy, the Selsky Memory Research Project, the Gladys Monroy and Larry Marks Center for Brain Disorders, the Advantage Trust, the Nella and Leon Benoziyo Center for Neurological Diseases, the David and Fela Shapell Family Center for Genetic Disorders Research, the Abish-Frenkel RNA center, the Andrea L. and Lawerence A. Wolfe Family Center for Research on Neuroimmunology and Neuromodulation, Weizmann - Center for Research on Neurodegeneration, the Brenden- Mann Women’s Innovation Impact Fund, The Irving B. Harris Fund for New Directions in Brain Research, the Irving Bieber, M.D. and Toby Bieber, M.D. Memorial Research Fund, The Leff Family, Barbara & Roberto Kaminitz, Sergio & Sônia Lozinsky, Debbie Koren, Jack and Lenore Lowenthal, and the Dears Foundation. A research grant from the Estates of Ethel H. Smith, Gerald Alexander, Mr. and Mrs. George Zbeda, David A. Fishstrom, Norman Fidelman, Hermine Miller, Olga Klein Astrachan, Hermine Miller, and The Maurice and Vivienne Wohl Biology Endowment, a research grant from Emily Merjan, the ISF grant (545/21), and the United States-Israel Binational Science Foundation (BSF; Grant No. 2023009), the support (O.R.). This research was supported by the Azrieli Institute for Brain and Neural Sciences (O.R., R.S., and I.S.). The Alzheimer’s Association Grant AARG-NTF-21-849529 supported the development of the MRI procedure (R.S.). Funding provided by BIRAX-Ageing supported the design and operation of the MPA apparatus (A.B.). Financial support for the computational studies was provided by the National Science Foundation via DMR-2204312 (J.M.S.).

All Science Journal Classification (ASJC) codes

General Chemistry
General Biochemistry,Genetics and Molecular Biology
General Physics and Astronomy

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Karlinski Zur, M., Bhattacharya, B., Solomonov, I., Ben Dror, S., Savidor, A., Levin, Y., Prior, A., Sapir, T., Harris, T., Olender, T., Schmidt, R., Schwarz, J. M., Sagi, I., Buxboim, A., & Reiner, O. (2025). Altered extracellular matrix structure and elevated stiffness in a brain organoid model for disease. Nature Communications, 16, Article 4094. https://doi.org/10.1038/s41467-025-59252-w

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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.",

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Karlinski Zur, M, Bhattacharya, B , Solomonov, I, Ben Dror, S, Savidor, A , Levin, Y, Prior, A, Sapir, T , Harris, T , Olender, T , Schmidt, R, Schwarz, JM, Sagi, I, Buxboim, A & Reiner, O 2025, 'Altered extracellular matrix structure and elevated stiffness in a brain organoid model for disease', Nature Communications, vol. 16, 4094. https://doi.org/10.1038/s41467-025-59252-w

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T1 - Altered extracellular matrix structure and elevated stiffness in a brain organoid model for disease

AU - Karlinski Zur, Maayan

AU - Bhattacharya, Bidisha

AU - Solomonov, Inna

AU - Ben Dror, Sivan

AU - Savidor, Alon

AU - Levin, Yishai

AU - Prior, Amir

AU - Sapir, Tamar

AU - Harris, Talia

AU - Olender, Tsviya

AU - Schmidt, Rita

AU - Schwarz, J. M.

AU - Sagi, Irit

AU - Buxboim, Amnon

AU - Reiner, Orly

PY - 2025/5/1

Y1 - 2025/5/1

N2 - 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.

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

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