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Abstract Recently, it has been recognized that natural extracellular matrix (ECM) and tissues are viscoelastic, while only elastic properties have been investigated in the past. How the viscoelastic matrix regulates stem cell patterning is critical for cell‐ECM mechano‐transduction. Here, this study fabricated different methacrylated hyaluronic acid (HA) hydrogels using covalent cross–linking, consisting of two gels with similar elasticity (stiffness) but different viscoelasticity, and two gels with similar viscoelasticity but different elasticity (stiffness). Meanwhile, a second set of dual network hydrogels are fabricated containing both covalent and coordinated cross–links. Human spinal cord organoid (hSCO) patterning in HA hydrogels and co‐culture with isogenic human blood vessel organoids (hBVOs) are investigated. The viscoelastic hydrogels promote regional hSCO patterning compared to the elastic hydrogels. More viscoelastic hydrogels can promote dorsal marker expression, while softer hydrogels result in higher interneuron marker expression. The effects of viscoelastic properties of the hydrogels become more dominant than the stiffness effects in the co‐culture of hSCOs and hBVOs. In addition, more viscoelastic hydrogels can lead to more Yes‐associated protein nuclear translocation, revealing the mechanism of cell‐ECM mechano‐transduction. This research provides insights into viscoelastic behaviors of the hydrogels during human organoid patterning with ECM‐mimicking in vitro microenvironments for applications in regenerative medicine.
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This content will become publicly available on May 28, 2026
Altered extracellular matrix structure and elevated stiffness in a brain organoid model for disease
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 byLIS1mutations, results in a smooth cortex. Here, we show that human-derived brain organoids withLIS1mutation 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 thatLIS1plays a critical role in ECM regulation during brain development and that its mutation leads to significant viscoelastic alterations.
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- Award ID(s):
- 2204312
- PAR ID:
- 10618168
- Publisher / Repository:
- Nature Portfolio
- Date Published:
- Journal Name:
- Nature Communications
- Volume:
- 16
- Issue:
- 1
- ISSN:
- 2041-1723
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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