1. Increased Extracellular Vesicles Mediate WNT5A Signaling in Idiopathic Pulmonary Fibrosis
- Author
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Joyce S. Lee, Jürgen Behr, Andreas Guenther, Axel Walch, Melanie Königshoff, Wolfgang Gesierich, Hoeke A. Baarsma, Florian Ciolek, Michaela Aichler, Sarah Hermann, Paul J. Wolters, Darcy E. Wagner, Thomas Höfer, Olivier Burgy, Michael Lindner, Marion Frankenberger, Mareike Lehmann, Martina M. De Santis, Christina M. Coughlan, and Aina Martin-Medina
- Subjects
EXPRESSION ,Adult ,Male ,0301 basic medicine ,Pulmonary and Respiratory Medicine ,FIBROBLASTS ,Critical Care and Intensive Care Medicine ,Wnt-5a Protein ,MECHANISMS ,PATHWAY ,ACTIVATION ,Extracellular matrix ,Extracellular Vesicles ,03 medical and health sciences ,Idiopathic pulmonary fibrosis ,Lung Fibrosis ,Exosomes ,Lung Fibroblasts ,Proliferation ,Wnt5a ,TGF beta signaling pathway ,Humans ,Medicine ,Secretion ,Fibroblast ,Cells, Cultured ,Aged ,EXOSOMES ,REPAIR ,Lung ,business.industry ,Wnt signaling pathway ,TGF-BETA ,Middle Aged ,respiratory system ,medicine.disease ,Idiopathic Pulmonary Fibrosis ,Microvesicles ,respiratory tract diseases ,030104 developmental biology ,medicine.anatomical_structure ,CELLS ,Cancer research ,SECRETION ,Female ,business ,Signal Transduction - 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-beta 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.
- Published
- 2018