title: Glycogen synthase kinase-3β/β-catenin signaling regulates neonatal lung mesenchymal stromal cell myofibroblastic differentiation.
abstract: In bronchopulmonary dysplasia (BPD), alveolar septa are thickened with collagen and α-smooth muscle actin-, transforming growth factor (TGF)-β-positive myofibroblasts. We examined the biochemical mechanisms underlying myofibroblastic differentiation, focusing on the role of glycogen synthase kinase-3β (GSK-3β)/β-catenin signaling pathway. In the cytoplasm, β-catenin is phosphorylated on the NH(2) terminus by constitutively active GSK-3β, favoring its degradation. Upon TGF-β stimulation, GSK-3β is phosphorylated and inactivated, allowing β-catenin to translocate to the nucleus, where it activates transcription of genes involved in myofibroblastic differentiation. We examined the role of β-catenin in TGF-β1-induced myofibroblastic differentiation of neonatal lung mesenchymal stromal cells (MSCs) isolated from tracheal aspirates of premature infants with respiratory distress. TGF-β1 increased β-catenin expression and nuclear translocation. Transduction of cells with GSK-3β S9A, a nonphosphorylatable, constitutively active mutant that favors β-catenin degradation, blocked TGF-β1-induced myofibroblastic differentiation. Furthermore, transduction of MSCs with ΔN-catenin, a truncation mutant that cannot be phosphorylated on the NH(2) terminus by GSK-3β and is not degraded, was sufficient for myofibroblastic differentiation. In vivo, hyperoxic exposure of neonatal mice increases expression of β-catenin in α-smooth muscle actin-positive myofibroblasts. Similar changes were found in lungs of infants with BPD. Finally, low-passage unstimulated MSCs from infants developing BPD showed higher phospho-GSK-3β, β-catenin, and α-actin content compared with MSCs from infants not developing this disease, and phospho-GSK-3β and β-catenin each correlated with α-actin content. We conclude that phospho-GSK-3β/β-catenin signaling regulates α-smooth muscle actin expression, a marker of myofibroblast differentiation, in vitro and in vivo. This pathway appears to be activated in lung mesenchymal cells from patients with BPD.
authors: Department of Pediatrics, University of Michigan Medical School, Ann Arbor, Michigan, USA.
authors: Antonia P
authors: AP
authors: Popova
authors: J Kelley
authors: JK
authors: Bentley
authors: Anuli C
authors: AC
authors: Anyanwu
authors: Michelle N
authors: MN
authors: Richardson
authors: Marisa J
authors: MJ
authors: Linn
authors: Jing
authors: J
authors: Lei
authors: Elizabeth J
authors: EJ
authors: Wong
authors: Adam M
authors: AM
authors: Goldsmith
authors: Gloria S
authors: GS
authors: Pryhuber
authors: Marc B
authors: MB
authors: Hershenson
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D001997:Bronchopulmonary Dysplasia / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D002454:Cell Differentiation; D002478:Cells, Cultured; D055513:Connective Tissue Growth Factor / Q000494:pharmacology / Q000502:physiology; D015870:Gene Expression; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism* / Q000502:physiology; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D018496:Hyperoxia / Q000378:metabolism / Q000473:pathology; D007231:Infant, Newborn; D008168:Lung / Q000201:enzymology / Q000378:metabolism / Q000473:pathology*; D059630:Mesenchymal Stem Cells / Q000201:enzymology / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D058628:Myofibroblasts; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D058258:Serpin E2 / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology / Q000502:physiology; D051176:beta Catenin / Q000378:metabolism*
chemical_list: D000199:Actins; C526317:CCN2 protein, human; D058258:Serpin E2; C511869:Serpine2 protein, mouse; D053773:Transforming Growth Factor beta1; D051176:beta Catenin; D055513:Connective Tissue Growth Factor; D019869:Phosphatidylinositol 3-Kinases; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3