title: Posttranslational modification of β-catenin is associated with pathogenic fibroblastic changes in bronchopulmonary dysplasia.
abstract: 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-cateninY489) 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-cateninY489in 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-cateninY489and 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-cateninY489is a durable marker of fibroblast activation in BPD and may play an important role in BPD disease pathobiology.
authors.affiliation: Mildred Stahlman Division of Neonatology, Department of Pediatrics, Vanderbilt University, Nashville, Tennessee; jennifer.sucre@vanderbilt.edu.
authors.forename: Jennifer M S
authors.initials: JM
authors.lastname: Sucre
authors.affiliation: UCLA Children's Discovery and Innovation Institute, Mattel Children's Hospital UCLA, Department of Pediatrics, David Geffen School of Medicine, UCLA, Los Angeles, California.|Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, California.
authors.forename: Preethi
authors.initials: P
authors.lastname: Vijayaraj
authors.affiliation: UCLA Children's Discovery and Innovation Institute, Mattel Children's Hospital UCLA, Department of Pediatrics, David Geffen School of Medicine, UCLA, Los Angeles, California.|UCLA Department of Molecular Biology Interdepartmental Program, UCLA, Los Angeles, California.
authors.forename: Cody J
authors.initials: CJ
authors.lastname: Aros
authors.affiliation: UCLA Department of Materials Science and Engineering, UCLA, Los Angeles, California.
authors.forename: Dan
authors.initials: D
authors.lastname: Wilkinson
authors.affiliation: UCLA Children's Discovery and Innovation Institute, Mattel Children's Hospital UCLA, Department of Pediatrics, David Geffen School of Medicine, UCLA, Los Angeles, California.
authors.forename: Manash
authors.initials: M
authors.lastname: Paul
authors.affiliation: UCLA Department of Materials Science and Engineering, UCLA, Los Angeles, California.
authors.forename: Bruce
authors.initials: B
authors.lastname: Dunn
authors.affiliation: Mildred Stahlman Division of Neonatology, Department of Pediatrics, Vanderbilt University, Nashville, Tennessee.
authors.forename: Susan H
authors.initials: SH
authors.lastname: Guttentag
authors.affiliation: UCLA Children's Discovery and Innovation Institute, Mattel Children's Hospital UCLA, Department of Pediatrics, David Geffen School of Medicine, UCLA, Los Angeles, California.|Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, California.|Pulmonary Medicine, David Geffen School of Medicine, UCLA, Los Angeles, California; and.|Eli and Edythe Broad Stem Cell Research Center, UCLA, Los Angeles, California.
authors.forename: Brigitte N
authors.initials: BN
authors.lastname: Gomperts
mesh_terms: D000199:Actins / Q000378:metabolism; D001997:Bronchopulmonary Dysplasia / Q000378:metabolism* / Q000473:pathology*; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D000069439:Dasatinib / Q000494:pharmacology; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D006801:Humans; D018496:Hyperoxia / Q000150:complications / Q000378:metabolism / Q000473:pathology; D000860:Hypoxia / Q000150:complications / Q000378:metabolism / Q000473:pathology; D007231:Infant, Newborn; D008168:Lung / Q000187:drug effects / Q000254:growth & development / Q000378:metabolism / Q000473:pathology; D009940:Organoids / Q000187:drug effects / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects; D060449:Wnt Signaling Pathway / Q000187:drug effects; D051176:beta Catenin / Q000378:metabolism*
chemical_list: D000199:Actins; D047428:Protein Kinase Inhibitors; D051176:beta Catenin; D000069439:Dasatinib
keywords: Wnt/β-catenin; bronchopulmonary dysplasia; disease modeling; fibrosis; hyperoxia