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Local photo-crosslinking of native tissue matrix regulates cell function.

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Early fibrotic lesions were mimicked by crosslinking extracellular matrix proteins. This process influenced epithelial cell behavior and extracellular matrix remodeling, offering insights into tissue fibrosis initiation.

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Area of Science:

  • Biomedical Engineering
  • Cell Biology
  • Tissue Engineering

Background:

  • The extracellular microenvironment's mechanical properties guide cell fate.
  • Fibrotic diseases involve extracellular matrix (ECM) changes like increased crosslinking.
  • Early fibrosis initiation is challenging to model due to difficulty recreating native ECM lesions.

Purpose of the Study:

  • To develop a method for recapitulating early fibrotic lesions in native tissues.
  • To investigate the role of ECM crosslinking in epithelial cell behavior during early fibrosis.
  • To explore implications for ex vivo disease modeling.

Main Methods:

  • Visible light-mediated photochemistry used for localized ECM protein crosslinking and stiffening.
  • Ex vivo murine and human tissue models employed.
  • Epithelial cell lineage-traced mice utilized to track cell fate.
  • Inhibition of cytoskeletal tension and integrin engagement.

Main Results:

  • Local ECM crosslinking mimicked early fibrotic lesions in ex vivo lung tissue.
  • Induced fibrosis increased alveolar epithelial cell spreading, differentiation, and ECM remodeling.
  • Inhibiting cytoskeletal tension or integrin engagement led to epithelial cell dedifferentiation and reduced ECM deposition.

Conclusions:

  • Local ECM crosslinking and remodeling play a critical role in early-stage tissue fibrosis.
  • Cytoskeletal tension and integrin signaling are key mediators of epithelial cell responses to ECM changes.
  • The findings support the development of ex vivo models for studying fibrosis and other tissue-related diseases.