Tenascin‐C Activation of Lung Fibroblasts in a 3D Synthetic Lung Extracellular Matrix Mimic

• Published in: Advanced materials (Weinheim) 2023-08, Vol.35 (33), p.e2301493-n/a
• Main Authors: Kundu, Aritra Nath, Dougan, Carey E., Mahmoud, Samar, Kilic, Alara, Panagiotou, Alexi, Richbourg, Nathan R., Irakoze, Ninette, Peyton, Shelly R.
• Format: Article
• Language: English
• Subjects: Binding; Biomechanics; Breast cancer; breast cancer metastasis; Breast Neoplasms; Combinatorial analysis; Extracellular matrix; Extracellular Matrix - metabolism; Female; Fibroblasts; Growth factors; Humans; Hydrogels; Hydrogels - chemistry; Integrins - metabolism; Lung; Lungs; Materials science; Matrix metalloproteinases; Metastasis; Peptides; Peptides - chemistry; poly(ethylene glycol); stiffness; Structural integrity; Tenascin - metabolism; Tenascin - pharmacology
• ISSN: 0935-9648; 1521-4095; 1521-4095
• DOI: 10.1002/adma.202301493

The lung extracellular matrix (ECM) maintains the structural integrity of the tissue and regulates the phenotype and functions of resident fibroblasts. Lung‐metastatic breast cancer alters these cell‐ECM interactions, promoting fibroblast activation. There is a need for bio‐instructive ECM models that match the ECM composition and biomechanics of the lung to study these cell‐matrix interactions in vitro. Here, a synthetic, bioactive hydrogel is synthesized that mimics the native lung modulus and includes a representative distribution of the most abundant ECM peptide motifs responsible for integrin‐binding and matrix metalloproteinase (MMP)‐mediated degradation in the lung, which enables quiescent culture of human lung fibroblasts (HLFs). Stimulation with transforming growth factor β1 (TGF‐β1), metastatic breast cancer conditioned media (CM), or tenascin‐C‐derived integrin‐binding peptide activated hydrogel‐encapsulated HLFs demonstrates multiple environmental methods to activate HLFs in a lung ECM‐mimicking hydrogel. This lung hydrogel platform is a tunable, synthetic approach to studying the independent and combinatorial effects of ECM in regulating fibroblast quiescence and activation. A hydrogel that mimics the protein content and stiffness of healthy lung tissue is synthesized. Lung‐mimicking material is applied to reveal the ability of tenascin‐C to activate fibroblasts in lung‐metastatic breast cancer. This novel hydrogel environment will be incredibly useful for research questions involving the lung extracellular matrix.