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

Author

Listed:
  • Maayan Karlinski Zur

    (Weizmann Institute of Science
    Weizmann Institute of Science
    Weizmann Institute)

  • Bidisha Bhattacharya

    (Weizmann Institute of Science
    Weizmann Institute)

  • 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
    Weizmann Institute)

  • Talia Harris

    (Weizmann Institute of Science)

  • Tsviya Olender

    (Weizmann Institute of Science)

  • Rita Schmidt

    (Weizmann Institute of Science
    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
    The Hebrew University of Jerusalem, The Edmond J. Safra Campus
    The Hebrew University of Jerusalem, The Edmond J. Safra Campus)

  • Orly Reiner

    (Weizmann Institute of Science
    Weizmann Institute)

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.

Suggested Citation

  • 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, 2025. "Altered extracellular matrix structure and elevated stiffness in a brain organoid model for disease," Nature Communications, Nature, vol. 16(1), pages 1-16, December.
  • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-59252-w
    DOI: 10.1038/s41467-025-59252-w
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    References listed on IDEAS

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