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αvβ3 Integrin drives fibroblast contraction and strain stiffening of soft provisional matrix during progressive fibrosis
Vincent F. Fiore, … , James S. Hagood, Thomas H. Barker
Vincent F. Fiore, … , James S. Hagood, Thomas H. Barker
Published October 18, 2018
Citation Information: JCI Insight. 2018;3(20):e97597. https://doi.org/10.1172/jci.insight.97597.
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Research Article Cell biology Pulmonology

αvβ3 Integrin drives fibroblast contraction and strain stiffening of soft provisional matrix during progressive fibrosis

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Abstract

Fibrosis is characterized by persistent deposition of extracellular matrix (ECM) by fibroblasts. Fibroblast mechanosensing of a stiffened ECM is hypothesized to drive the fibrotic program; however, the spatial distribution of ECM mechanics and their derangements in progressive fibrosis are poorly characterized. Importantly, fibrosis presents with significant histopathological heterogeneity at the microscale. Here, we report that fibroblastic foci (FF), the regions of active fibrogenesis in idiopathic pulmonary fibrosis (IPF), are surprisingly of similar modulus as normal lung parenchyma and are nonlinearly elastic. In vitro, provisional ECMs with mechanical properties similar to those of FF activate both normal and IPF patient–derived fibroblasts, whereas type I collagen ECMs with similar mechanical properties do not. This is mediated, in part, by αvβ3 integrin engagement and is augmented by loss of expression of Thy-1, which regulates αvβ3 integrin avidity for ECM. Thy-1 loss potentiates cell contractility-driven strain stiffening of provisional ECM in vitro and causes elevated αvβ3 integrin activation, increased fibrosis, and greater mortality following fibrotic lung injury in vivo. These data suggest a central role for αvβ3 integrin and provisional ECM in overriding mechanical cues that normally impose quiescent phenotypes, driving progressive fibrosis through physical stiffening of the fibrotic niche.

Authors

Vincent F. Fiore, Simon S. Wong, Coleen Tran, Chunting Tan, Wenwei Xu, Todd Sulchek, Eric S. White, James S. Hagood, Thomas H. Barker

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Figure 6

Thy-1 loss elevates αvβ3 integrin activity and causes progressive fibrosis in a model of lung fibrosis.

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Thy-1 loss elevates αvβ3 integrin activity and causes progressive fibro...
(A) Immunofluorescence images of active αvβ3 (WOW-1 Ab, green), α-SMA (red), and nuclei (blue) in lung tissue sections in WT and Thy-1–/– mice at 0, 14, and 42 days after intratracheal bleomycin treatment to induce fibrosis. A magnified image (yellow box) of active αvβ3 is shown (gray, right). Original magnification, ×20. (B) Quantification of WOW-1 staining intensity in WT (black outline) and Thy-1–/– (red outline) lungs at 14, 28, 42, and 56 days following bleomycin treatment. (C) H&E and Mason’s trichrome staining of WT and Thy-1–/– mice 14 and 42 days after bleomycin treatment. Note sustained alveolar destruction and connective tissue deposition in Thy-1–/– lungs 42 days after bleomycin, while WT lungs are largely normal. Original magnification, ×10. (D) Quantification of pulmonary elastic resistance from whole-lung forced oscillation maneuvers in WT and Thy-1–/– mice over time after bleomycin treatment. (E) Kaplan-Meyer survival curve for WT and Thy-1–/– mice after bleomycin treatment. Error bars are SEM.

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