Posttranslational modification of β-catenin is associated with pathogenic fibroblastic changes in bronchopulmonary dysplasia

• Published in: American journal of physiology. Lung cellular and molecular physiology Vol. 312; no. 2; pp. L186 - L195
• Main Authors: Sucre, Jennifer M S, Vijayaraj, Preethi, Aros, Cody J, Wilkinson, Dan, Paul, Manash, Dunn, Bruce, Guttentag, Susan H, Gomperts, Brigitte N
• Format: Journal Article
• Language: English
• Published: United States American Physiological Society 01.02.2017
• Subjects: Actins - metabolism; beta Catenin - metabolism; Bronchopulmonary Dysplasia - metabolism; Bronchopulmonary Dysplasia - pathology; Cell Nucleus - drug effects; Cell Nucleus - metabolism; Dasatinib - pharmacology; Fibroblasts - drug effects; Fibroblasts - metabolism; Fibroblasts - pathology; Humans; Hyperoxia - complications; Hyperoxia - metabolism; Hyperoxia - pathology; Hypoxia - complications; Hypoxia - metabolism; Hypoxia - pathology; Infant, Newborn; Lung - drug effects; Lung - growth & development; Lung - metabolism; Lung - pathology; Organoids - drug effects; Organoids - metabolism; Phosphorylation - drug effects; Protein Kinase Inhibitors - pharmacology; Protein Processing, Post-Translational - drug effects; Protein Transport - drug effects; Rapid Report; Up-Regulation - drug effects; Wnt Signaling Pathway - drug effects; fibrosis; hyperoxia; bronchopulmonary dysplasia; Wnt/β-catenin; disease modeling
• ISSN: 1040-0605; 1522-1504
• DOI: 10.1152/ajplung.00477.2016

Bronchopulmonary dysplasia (BPD) is a common complication of premature birth. The histopathology of BPD is characterized by an arrest of alveolarization with fibroblast activation. The Wnt/β-catenin signaling pathway is important in early lung development. When Wnt signaling is active, phosphorylation of β-catenin by tyrosine kinases at activating sites, specifically at tyrosine 489 (Y489), correlates with nuclear localization of β-catenin. We examined fetal lung tissue, lung tissue from term newborns, and lung tissue from infants who died with BPD; we found nuclear β-catenin phosphorylation at Y489 in epithelial and mesenchymal cells in fetal tissue and BPD tissue, but not in the lungs of term infants. Using a 3D human organoid model, we found increased nuclear localization of β-catenin phosphorylated at Y489 (p-β-catenin ) after exposure to alternating hypoxia and hyperoxia compared with organoids cultured in normoxia. Exogenous stimulation of the canonical Wnt pathway in organoids was sufficient to cause nuclear localization of p-β-catenin in normoxia and mimicked the pattern of α-smooth muscle actin (α-SMA) expression seen with fibroblastic activation from oxidative stress. Treatment of organoids with a tyrosine kinase inhibitor prior to cyclic hypoxia-hyperoxia inhibited nuclear localization of p-β-catenin and prevented α-SMA expression by fibroblasts. Posttranslational phosphorylation of β-catenin is a transient feature of normal lung development. Moreover, the persistence of p-β-catenin is a durable marker of fibroblast activation in BPD and may play an important role in BPD disease pathobiology.