scholarly journals Cigarette Smoke Activates NOTCH3 to Promote Goblet Cell Differentiation in Human Airway Epithelial Cells

2020 ◽  
Author(s):  
Manish Bodas ◽  
Andrew R. Moore ◽  
Bharathiraja Subramaniyan ◽  
Constantin Georgescu ◽  
Jonathan D. Wren ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
Epithelial Cells ◽  
Notch Signaling ◽  
Cigarette Smoke ◽  
Goblet Cell ◽  
Airway Epithelium ◽  
The United States ◽  
Dependent Manner ◽  
Over Expression ◽  
Goblet Cell Differentiation

AbstractChronic obstructive pulmonary disease (COPD) is the 3rd leading cause of death in the United States and is primarily caused by cigarette smoking. Increased numbers of mucus-producing secretory (“goblet”) cells defined as goblet cell metaplasia or hyperplasia (GCMH), contributes significantly to COPD pathophysiology. The objective of this study was to determine whether NOTCH signaling regulates goblet cell differentiation in response to cigarette smoke. Primary human bronchial epithelial cells (HBECs) from nonsmokers and COPD smokers were differentiated in vitro on air-liquid interface and exposed to cigarette smoke extract (CSE) for 7 days. NOTCH signaling activity was modulated using (1) the NOTCH/γ-secretase inhibitor Dibenzazepine (DBZ), (2) lentiviral over-expression of the NOTCH3-intracellular domain (NICD3) or (3) NOTCH3-specific siRNA. Cell differentiation and response to CSE were evaluated by qPCR, Western blotting, immunostaining and RNA-Seq. We found that CSE exposure of nonsmoker airway epithelium induced goblet cell differentiation characteristic of GCMH. Treatment with DBZ suppressed CSE-dependent induction of goblet cell differentiation. Furthermore, CSE induced NOTCH3 activation, as revealed by increased NOTCH3 nuclear localization and elevated NICD3 protein levels. Over-expression of NICD3 increased the expression of goblet cell associated genes SPDEF and MUC5AC, whereas NOTCH3 knockdown suppressed CSE-mediated induction of SPDEF and MUC5AC. Finally, CSE exposure of COPD airway epithelium induced goblet cell differentiation in a NOTCH3-dependent manner. These results identify NOTCH3 activation as one of the important mechanisms by which cigarette smoke induces goblet cell differentiation, thus providing a novel potential strategy to control GCMH-related pathologies in smokers and patients with COPD.

scholarly journals P105 Glutathione S-transferase theta 1 protects against colitis through goblet cell differentiation via interleukin-22

2020 ◽  
Vol 14 (Supplement_1) ◽  
pp. S188-S188
Author(s):  
J H Kim ◽  
J B Ahn ◽  
D H Kim ◽  
S Kim ◽  
H W Ma ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
Immune Responses ◽  
Goblet Cell ◽  
Goblet Cells ◽  
Dependent Manner ◽  
Glutathione S Transferase ◽  
Host Immune Responses ◽  
Interleukin 22 ◽  
Gstt1 Gene ◽  
Goblet Cell Differentiation

Abstract Background The enzyme glutathione S-transferase theta 1 (GSTT1) is involved in detoxifying chemicals, including reactive oxygen species (ROS). Oxidative stress plays a key role in the pathogenesis of inflammatory bowel disease (IBD). Although mutation of the GSTT1 gene increases IBD susceptibility, the underlying mechanisms remain unexplained. Methods The Gstt1 gene was intrarectally or intraperitoneally delivered to mice with dextran sodium sulphate (DSS)-induced colitis. The GSTT1 gene was knocked down or knocked out using short interfering RNA or genome editing, respectively. Protein and mRNA expression and differentiation of goblet cells were evaluated. Results We identified decreased expression of GSTT1 in inflamed tissues from IBD patients and mice compared with their control counterparts, respectively. We also noted attenuation of colitis through gene transfer of Gstt1 to DSS-treated mice via the interleukin-22 (IL-22) pathway. GSTT1 was differently regulated by pathogens and host immune responses. Down-regulation of GSTT1 reduced innate defence responses and goblet cell differentiation. The GSTT1 mutation in intestinal epithelial cells as well as IBD patients diminished its dimerisation, which was connected to insufficient phosphorylation of signal transducer and activator of transcription 3 and p38/mitogen-activated protein kinase by their common activator, IL-22. Conclusion GSTT1 ameliorated IL-22 in colitis in a dependent manner and contributed as a modulator of goblet cells through sensing pathogens and host immune responses. Its mutations are linked to chronic intestinal inflammation due to its insufficient dimerisation. Our results provide new insights into GSTT1 mutations and their functional consequences in IBDs.

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.

606 KLF4 Is a Downstream Target of the Notch Signaling Pathway That Controls Goblet Cell Differentiation in the Mouse GI Tract

2008 ◽  
Vol 134 (4) ◽  
pp. A-84
Author(s):  
Xiangdong Yang ◽  
David M. Pritchard ◽  
Shigeo Takaishi ◽  
shuiping Tu ◽  
Frédéric Marrache ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
Notch Signaling ◽  
Signaling Pathway ◽  
Goblet Cell ◽  
Notch Signaling Pathway ◽  
Gi Tract ◽  
Downstream Target ◽  
Goblet Cell Differentiation

scholarly journals Prenatal Secondhand Cigarette Smoke Promotes Th2 Polarization and Impairs Goblet Cell Differentiation and Airway Mucus Formation

2011 ◽  
Vol 187 (9) ◽  
pp. 4542-4552 ◽  
Author(s):  
Shashi P. Singh ◽  
Sravanthi Gundavarapu ◽  
Juan C. Peña-Philippides ◽  
Jules Rir-sima-ah ◽  
Neerad C. Mishra ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
Cigarette Smoke ◽  
Goblet Cell ◽  
Th2 Polarization ◽  
Goblet Cell Differentiation ◽  
Airway Mucus

Delta-like 1 expression promotes goblet cell differentiation in Notch-inactivated human colonic epithelial cells

2010 ◽  
Vol 393 (4) ◽  
pp. 662-667 ◽  
Author(s):  
Junko Akiyama ◽  
Ryuichi Okamoto ◽  
Michiko Iwasaki ◽  
Xiu Zheng ◽  
Shiro Yui ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
Epithelial Cells ◽  
Goblet Cell ◽  
Colonic Epithelial Cells ◽  
Goblet Cell Differentiation
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