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

Abstract

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.

Dynamic 3D in vitro lung models: applications of inorganic nanoparticles for model development and characterization

“…[118][119][120][121][122][123][124] Recently, Kundu and colleagues developed a sophisticated approach to model BC lung metastasis, based on a synthetic biomimetic PEG-hydrogel, functionalized with a peptide mixture to improve adhesion and cell-mediated ECM remodelling. 125 For this purpose, the authors initially identified core adhesion and cleavable peptides present in healthy human lung ECM samples (Fig. 5A).…”