Aina Martin-Medina1, Mareike Lehmann1, Olivier Burgy2, Sarah Hermann1, Hoeke A Baarsma1, Darcy E Wagner1, Martina M De Santis1, Florian Ciolek1, Thomas P Hofer1,3, Marion Frankenberger1, Michaela Aichler4, Michael Lindner3, Wolfgang Gesierich3, Andreas Guenther5,6,7, Axel Walch4, Christina Coughlan8, Paul Wolters9, Joyce S Lee2, Jürgen Behr1,3, Melanie Königshoff1,2. 1. Comprehensive Pneumology Center, Ludwig Maximilian University, University Hospital Grosshadern, and Helmholtz Center Munich, member of the German Center of Lung Research, Munich, Germany. 2. Division of Pulmonary Sciences and Critical Care Medicine, Department of Medicine, and. 3. Center for Thoracic Surgery, Asklepios Biobank for Lung Diseases, Asklepios Clinic Munich-Gauting, Munich, Germany. 4. Institute of Pathology, Research Unit Analytical Pathology, Helmholtz Center Munich, Munich, Germany. 5. Department of Internal Medicine, Universities of Giessen and Marburg Lung Center, Justus Liebig University of Giessen, member of the German Center for Lung Research, Giessen, Germany. 6. Agaplesion Lung Clinic Waldhof Elgershausen, Greifenstein, Germany. 7. European IPF Network and European IPF Registry, Giessen, Germany; and. 8. Department of Neurology, University of Colorado Denver, Aurora, Colorado. 9. Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of California San Francisco, San Francisco, California.
Abstract
Rationale: Idiopathic pulmonary fibrosis (IPF) is a lethal lung disease characterized by lung epithelial cell injury, increased (myo)fibroblast activation, and extracellular matrix deposition. Extracellular vesicles (EVs) regulate intercellular communication by carrying a variety of signaling mediators, including WNT (wingless/integrated) proteins. The relevance of EVs in pulmonary fibrosis and their potential contribution to disease pathogenesis, however, remain unexplored. Objectives: To characterize EVs and study the role of EV-bound WNT signaling in IPF. Methods: We isolated EVs from BAL fluid (BALF) from experimental lung fibrosis as well as samples from IPF, non-IPF interstitial lung disease (ILD), non-ILD, and healthy volunteers from two independent cohorts. EVs were characterized by transmission electron microscopy, nanoparticle tracking analysis, and Western blotting. Primary human lung fibroblasts (phLFs) were used for EV isolation and analyzed by metabolic activity assays, cell counting, quantitative PCR, and Western blotting upon WNT gain- and loss-of-function studies.Measurements and Main Results: We found increased EVs, particularly exosomes, in BALF from experimental lung fibrosis as well as from patients with IPF. WNT5A was secreted on EVs in lung fibrosis and induced by transforming growth factor-β in primary human lung fibroblasts. The phLF-derived EVs induced phLF proliferation, which was attenuated by WNT5A silencing and antibody-mediated inhibition and required intact EV structure. Similarly, EVs from IPF BALF induced phLF proliferation, which was mediated by WNT5A.Conclusions: Increased EVs function as carriers for signaling mediators, such as WNT5A, in IPF and thus contribute to disease pathogenesis. Characterization of EV secretion and composition may lead to novel approaches to diagnose and develop treatments for pulmonary fibrosis.
Rationale: Idiopathic pulmonary fibrosis (IPF) is a lethal lung disease characterized by lung epithelial cell injury, increased (myo)fibroblast activation, and extracellular matrix deposition. Extracellular vesicles (EVs) regulate intercellular communication by carrying a variety of signaling mediators, including WNT (wingless/integrated) proteins. The relevance of EVs in pulmonary fibrosis and their potential contribution to disease pathogenesis, however, remain unexplored. Objectives: To characterize EVs and study the role of EV-bound WNT signaling in IPF. Methods: We isolated EVs from BAL fluid (BALF) from experimental lung fibrosis as well as samples from IPF, non-IPF interstitial lung disease (ILD), non-ILD, and healthy volunteers from two independent cohorts. EVs were characterized by transmission electron microscopy, nanoparticle tracking analysis, and Western blotting. Primary human lung fibroblasts (phLFs) were used for EV isolation and analyzed by metabolic activity assays, cell counting, quantitative PCR, and Western blotting upon WNT gain- and loss-of-function studies.Measurements and Main Results: We found increased EVs, particularly exosomes, in BALF from experimental lung fibrosis as well as from patients with IPF. WNT5A was secreted on EVs in lung fibrosis and induced by transforming growth factor-β in primary human lung fibroblasts. The phLF-derived EVs induced phLF proliferation, which was attenuated by WNT5A silencing and antibody-mediated inhibition and required intact EV structure. Similarly, EVs from IPF BALF induced phLF proliferation, which was mediated by WNT5A.Conclusions: Increased EVs function as carriers for signaling mediators, such as WNT5A, in IPF and thus contribute to disease pathogenesis. Characterization of EV secretion and composition may lead to novel approaches to diagnose and develop treatments for pulmonary fibrosis.
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