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

Area of Science:

• Neurodevelopmental Biology
• Biophysics
• Biomaterials Science

Background:

• Tissue viscoelasticity impacts cell behavior and morphology.
• Understanding viscoelastic changes in brain malformations like lissencephaly is crucial.
• Lissencephaly, characterized by a smooth cortex, arises from LIS1 mutations.

Purpose of the Study:

• To investigate the viscoelastic properties of human-derived brain organoids with LIS1 mutations.
• To explore the relationship between LIS1 mutations, extracellular matrix (ECM) organization, and mechanical changes.
• To assess the therapeutic potential of MMP9 in normalizing altered viscoelasticity.

Main Methods:

• Generation and characterization of human-derived brain organoids with LIS1 mutations.
• Measurement of tissue stiffness and water content using diffusion-weighted MRI.
• Analysis of extracellular matrix (ECM) expression and organization.
• Application of a computational microstructure mechanical model.
• Assessment of MMP9 treatment effects on viscoelastic properties.

Main Results:

• LIS1-mutated brain organoids exhibited significantly increased stiffness and water diffusion compared to controls.
• Abnormal ECM expression and organization were observed in mutated organoids.
• MMP9 treatment effectively reduced both stiffness and water diffusion to control levels.
• Computational modeling supported the link between ECM organization and mechanical changes.

Conclusions:

• LIS1 is critical for regulating ECM during brain development.
• LIS1 mutations lead to significant alterations in brain tissue viscoelasticity.
• Targeting MMP9 may offer a therapeutic strategy for LIS1-related brain malformations.