2. Academic Validation
  3. Local photocrosslinking of native tissue matrix regulates lung epithelial cell mechanosensing and function

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

  • Nat Mater. 2025 Sep 5. doi: 10.1038/s41563-025-02329-0.
Donia W Ahmed # 1,  Matthew L Tan # 2,  Yuchen Liu 3,  Jackson Gabbard 1,  Esther Gao 1,  Avinava Roy 2,  Michael M Hu 1,  Firaol S Midekssa 1,  Miriam Stevens 1,  Fulei Wuchu 1,  Minal Nenwani 1,  Jingyi Xia 1,  Adam Abraham 4,  Deepak Nagrath 1,  Lin Han 3,  Rachel L Zemans 5 6,  Brendon M Baker 1,  Claudia Loebel 7 8 9
Affiliations

Affiliations

  • 1 Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, USA.
  • 2 Department of Materials Science and Engineering, University of Michigan, Ann Arbor, MI, USA.
  • 3 School of Biomedical Engineering, Science and Health Systems, Drexel University, Philadelphia, PA, USA.
  • 4 Department of Orthopedics, University of Michigan, Ann Arbor, MI, USA.
  • 5 Cellular and Molecular Biology Program, University of Michigan, Ann Arbor, MI, USA.
  • 6 Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA.
  • 7 Department of Materials Science and Engineering, University of Michigan, Ann Arbor, MI, USA. loebelcl@seas.upenn.edu.
  • 8 Department of Bioengineering, University of Pennsylvania, Philadelphia, PA, USA. loebelcl@seas.upenn.edu.
  • 9 Center for Precision Engineering for Health, Philadelphia, PA, USA. loebelcl@seas.upenn.edu.
  • # Contributed equally.
PMID: 40913159 DOI: 10.1038/s41563-025-02329-0
Abstract

Within most tissues, the extracellular microenvironment provides mechanical cues that guide cell fate and function. Changes in the extracellular matrix such as aberrant deposition, densification and increased crosslinking are hallmarks of late-stage fibrotic diseases that often lead to organ dysfunction. Biomaterials have been widely used to mimic the mechanical properties of the fibrotic matrix and study pathophysiologic cell function. However, the initiation of fibrosis has largely been overlooked, due to challenges in recapitulating early stages of disease progression within the native extracellular microenvironment. Here, using visible-light-mediated photochemistry, we induced local crosslinking and stiffening of extracellular matrix proteins within ex vivo mouse and human lung tissue. In ex vivo lung tissue of epithelial cell lineage-traced mice, local matrix crosslinking mimicked early fibrotic lesions that increased alveolar epithelial cell mechanosensing, differentiation, and nascent protein deposition and remodelling. However, the inhibition of cytoskeletal tension, mechanosensitive signalling pathways or Integrin engagement reduced epithelial cell spreading and differentiation. Our findings emphasize the role of local extracellular matrix crosslinking and nascent protein deposition in early stage tissue fibrosis and have implications for ex vivo disease modelling and applications to Other tissues.

Figures
Products