Local photocrosslinking of native tissue matrix regulates lung epithelial cell mechanosensing and function

Area of Science:

• Biomedical Engineering
• Cell Biology
• Tissue Engineering

Background:

• The extracellular microenvironment's mechanical properties influence cell behavior.
• Fibrotic diseases involve extracellular matrix (ECM) changes, but early stages are poorly understood.
• Current models often overlook early fibrosis initiation within native tissue contexts.

Purpose of the Study:

• To investigate the role of early extracellular matrix (ECM) stiffening in tissue fibrosis initiation.
• To develop a method for recapitulating early fibrotic changes in native lung tissue.
• To understand how cells respond to localized ECM stiffening in early fibrosis.

Main Methods:

• Utilized visible-light-mediated photochemistry to induce localized ECM crosslinking and stiffening in ex vivo mouse and human lung tissue.
• Employed epithelial cell lineage-traced mice to track cellular responses.
• Manipulated cytoskeletal tension, mechanosensitive pathways, and integrin signaling to assess their impact on cell behavior.

Main Results:

• Local ECM crosslinking mimicked early fibrotic lesions in lung tissue.
• Induced stiffening enhanced alveolar epithelial cell mechanosensing, differentiation, and protein remodeling.
• Inhibiting cytoskeletal tension, specific signaling pathways, or integrin engagement reduced epithelial cell spreading and differentiation.

Conclusions:

• Local ECM crosslinking and associated protein deposition are critical drivers of early-stage tissue fibrosis.
• These findings highlight the importance of mechanical cues in fibrosis initiation.
• The study provides a valuable ex vivo model for studying early fibrosis and has broader implications for tissue engineering.