Tenascin-C activation of lung fibroblasts in a 3D synthetic lung extracellular matrix mimic

Author:

Kundu Aritra Nath,Dougan Carey E.,Mahmoud Samar,Kilic Alara,Panagiotou Alexi,Irakoze Ninette,Richbourg Nathan,Peyton Shelly R.

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 contain the ECM composition and biomechanics of the lung to study these cell-matrix interactionsin vitro. Here, we developed a synthetic, bioactive hydrogel 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 promotes quiescence of human lung fibroblasts (HLFs). Stimulation with transforming growth factor β1 (TGF-β1), metastatic breast cancer conditioned media (CM), or tenascin-C activated these hydrogel-encapsulated HLFs in a manner reflective of their nativein vivoresponses. We propose this lung hydrogel platform as a tunable, synthetic approach to study the independent and combinatorial effects of ECM in regulating fibroblast quiescence and activation.

Publisher

Cold Spring Harbor Laboratory

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