β-Catenin regulates differentiation of respiratory epithelial cells in vivo

2005 ◽  
Vol 289 (6) ◽  
pp. L971-L979 ◽  
Author(s):  
Michael L. Mucenski ◽  
Jennifer M. Nation ◽  
Angela R. Thitoff ◽  
Valérie Besnard ◽  
Yan Xu ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Goblet Cell ◽  
Alveolar Type ◽  
Type Ii ◽  
Respiratory Epithelial Cells ◽  
Cell Hyperplasia ◽  
Goblet Cell Hyperplasia ◽  
Air Space ◽  
Respiratory Epithelial ◽  
Conducting Airways

An activated form of β-catenin [CatnbΔ(ex3)] was expressed in respiratory epithelial cells of the developing lung. Although morphogenesis was not altered at birth, air space enlargement and epithelial cell dysplasia were observed in the early postnatal period and persisted into adulthood. The CatnbΔ(ex3) protein caused squamous, cuboidal, and goblet cell dysplasia in intrapulmonary conducting airways. Atypical epithelial cells that stained for surfactant pro protein C (pro-SP-C) and had morphological characteristics of alveolar type II cells were observed in bronchioles of the transgenic mice. CatnbΔ(ex3) inhibited expression of Foxa2 and caused goblet cell hyperplasia associated with increased staining for mucins and the MUC5A/C protein. In vitro, both wild type and activated β-catenin negatively regulated the expression of the Foxa2 promoter. CatnbΔ(ex3) also caused pulmonary tumors in adult mice. Activation of β-catenin caused ectopic differentiation of alveolar type II-like cells in conducting airways, goblet cell hyperplasia, and air space enlargement, demonstrating a critical role for the Wnt/β-catenin signal transduction pathway in the differentiation of the respiratory epithelium in the postnatal lung.

Laminin α-chain expression and basement membrane formation by MLE-15 respiratory epithelial cells

2002 ◽  
Vol 282 (5) ◽  
pp. L1004-L1011 ◽  
Author(s):  
Nguyet M. Nguyen ◽  
Yushi Bai ◽  
Katsumi Mochitate ◽  
Robert M. Senior
Keyword(s):  
Epithelial Cells ◽  
Basement Membrane ◽  
Critical Role ◽  
Basement Membranes ◽  
Alveolar Type ◽  
Type Ii Cells ◽  
Type Ii ◽  
Respiratory Epithelial Cells ◽  
Alveolar Type Ii Cells ◽  
Respiratory Epithelial

Basement membranes have a critical role in alveolar structure and function. Alveolar type II cells make basement membrane constituents, including laminin, but relatively little is known about the production of basement membrane proteins by murine alveolar type II cells and a convenient system is not available to study basement membrane production by murine alveolar type II cells. To facilitate study of basement membrane production, with particular focus on laminin chains, we examined transformed murine distal respiratory epithelial cells (MLE-15), which have many structural and biochemical features of alveolar type II cells. We found that MLE-15 cells produce laminin-α5, a trace amount of laminin-α3, laminins-β1 and -γ1, type IV collagen, and perlecan. Transforming growth factor-β1 significantly induces expression of laminin-α1. When grown on a fibroblast-embedded collagen gel, MLE-15 cells assemble a basement membrane-like layer containing laminin-α5. These findings indicate that MLE-15 cells will be useful in modeling basement membrane production and assembly by alveolar type II cells.

scholarly journals WNT/RYK signaling restricts goblet cell differentiation during lung development and repair

2019 ◽  
Vol 116 (51) ◽  
pp. 25697-25706 ◽  
Author(s):  
Hyun-Taek Kim ◽  
Wenguang Yin ◽  
Yuko Nakamichi ◽  
Paolo Panza ◽  
Beate Grohmann ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
Epithelial Cells ◽  
Goblet Cell ◽  
Lung Development ◽  
Alveolar Epithelial Cells ◽  
Airway Epithelial ◽  
Cell Hyperplasia ◽  
Mucus Hypersecretion ◽  
Goblet Cell Hyperplasia ◽  
Goblet Cell Differentiation

Goblet cell metaplasia and mucus hypersecretion are observed in many pulmonary diseases, including asthma, chronic obstructive pulmonary disease (COPD), and cystic fibrosis. However, the regulation of goblet cell differentiation remains unclear. Here, we identify a regulator of this process in anN-ethyl-N-nitrosourea (ENU) screen for modulators of postnatal lung development;Rykmutant mice exhibit lung inflammation, goblet cell hyperplasia, and mucus hypersecretion. RYK functions as a WNT coreceptor, and, in the developing lung, we observed high RYK expression in airway epithelial cells and moderate expression in mesenchymal cells as well as in alveolar epithelial cells. From transcriptomic analyses and follow-up studies, we found decreased WNT/β-catenin signaling activity in the mutant lung epithelium. Epithelial-specificRykdeletion causes goblet cell hyperplasia and mucus hypersecretion but not inflammation, while club cell-specificRykdeletion in adult stages leads to goblet cell hyperplasia and mucus hypersecretion during regeneration. We also found that the airway epithelium of COPD patients often displays goblet cell metaplastic foci, as well as reduced RYK expression. Altogether, our findings reveal that RYK plays important roles in maintaining the balance between airway epithelial cell populations during development and repair, and that defects in RYK expression or function may contribute to the pathogenesis of human lung diseases.

STAT-3 regulates surfactant phospholipid homeostasis in normal lung and during endotoxin-mediated lung injury

2008 ◽  
Vol 104 (6) ◽  
pp. 1753-1760 ◽  
Author(s):  
Machiko Ikegami ◽  
Angelica Falcone ◽  
Jeffrey A. Whitsett
Keyword(s):  
Epithelial Cells ◽  
Lung Injury ◽  
Critical Role ◽  
Lung Mechanics ◽  
Normal Lung ◽  
Type Ii Cells ◽  
Type Ii ◽  
Phospholipid Synthesis ◽  
Respiratory Epithelial Cells ◽  
Respiratory Epithelial

Acute lung injury associated with surfactant deficiency remains a major cause of pulmonary morbidity and mortality. Since signal transducer and activator of transcription-3 (STAT-3) plays an important role in protecting respiratory epithelial cells during injury, we hypothesized that STAT-3 may regulate gene expression in type II cells that mediate surfactant phospholipid synthesis. Conditional deletion of Stat-3 in respiratory epithelial cells in the lung of transgenic mice ( Stat-3Δ/Δ mice) decreased surfactant phospholipid synthesis and secretion. Deletion of Stat-3 was associated with decreased expression of Akt2, Srebf-1, and other genes expressed in type II cells that may influence surfactant phospholipid synthesis ( Glut-1, Slc34a2, Gpam, Acox2, and Cds2). Stat-3Δ/Δ mice were more susceptible to intratracheal lipopolysaccharide (LPS). Saturated phosphatidylcholine and surfactant protein B levels were significantly decreased in bronchoalveolar lavage fluid from LPS-treated Stat-3Δ/Δ mice. Alveolar capillary leak, proinflammatory cytokine expression, and perturbations of lung mechanics caused by LPS were exacerbated after deletion of STAT-3. STAT-3 plays a critical role in the regulation of surfactant lipid synthesis in the normal lung and during lung injury caused by LPS.

GM-CSF enhances lung growth and causes alveolar type II epithelial cell hyperplasia in transgenic mice

1997 ◽  
Vol 273 (4) ◽  
pp. L715-L725 ◽  
Author(s):  
Jacquelyn A. Huffman Reed ◽  
Ward R. Rice ◽  
Zsuzsanna K. Zsengellér ◽  
Susan E. Wert ◽  
Glenn Dranoff ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Transgenic Mice ◽  
Lung Epithelial Cells ◽  
Alveolar Type ◽  
Type Ii Cells ◽  
Type Ii ◽  
Cell Hyperplasia ◽  
Α Subunit ◽  
Gm Csf ◽  
Type Ii Cell

The human surfactant protein (SP)-C gene promoter was used to direct expression of mouse granulocyte macrophage colony-stimulating factor (GM-CSF; SP-C-GM mice) in lung epithelial cells in GM-CSF-replete (GM+/+) or GM-CSF null mutant (GM−/−) mice. Lung weight and volume were significantly increased in SP-C-GM mice compared with GM+/+ or GM−/− control mice. Immunohistochemical staining demonstrated marked type II cell hyperplasia, and immunofluorescent labeling for proliferating cell nuclear antigen was increased in type II cells of SP-C-GM mice. Abundance of type II cells per mouse lung was increased three- to fourfold in SP-C-GM mice compared with GM+/+ and GM−/− mice. GM-CSF increased bromodeoxyuridine labeling of isolated type II cells in vitro. Type II cells, alveolar macrophages, and endothelial and bronchiolar epithelial cells were stained by antibodies to the GM-CSF receptor α-subunit in both GM+/+ mice and GM-CSF gene-targeted mice that are also homozygous for the SP-C-GM transgene. High levels of GM-CSF expression in type II cells of transgenic mice increased lung size and caused type II cell hyperplasia, demonstrating an unexpected role for the molecule in the regulation of type II cell proliferation and differentiation.

Interleukin-33 induces mucin gene expression and goblet cell hyperplasia in human nasal epithelial cells

Cytokine ◽  
2017 ◽  
Vol 90 ◽  
pp. 60-65 ◽  
Author(s):  
Hajime Ishinaga ◽  
Masako Kitano ◽  
Masaaki Toda ◽  
Corina N. D’Alessandro-Gabazza ◽  
Esteban C. Gabazza ◽  
...  
Keyword(s):  
Gene Expression ◽  
Epithelial Cells ◽  
Goblet Cell ◽  
Cell Hyperplasia ◽  
Goblet Cell Hyperplasia ◽  
Nasal Epithelial Cells ◽  
Interleukin 33 ◽  
Mucin Gene ◽  
Human Nasal Epithelial Cells
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