scholarly journals Transcription factors involved in stem cell maintenance are downstream of Slug/Snail2 and repressed by TGF-β in bronchial epithelial progenitors from Chronic Obstructive Pulmonary Disease

2019 ◽  
Author(s):  
Pierre de la Grange ◽  
Ariane Jolly ◽  
Charlotte Courageux ◽  
Chamseddine Ben Brahim ◽  
Pascale LEROY
Keyword(s):  
Chronic Obstructive Pulmonary Disease ◽  
Stem Cell ◽  
Transcription Factors ◽  
Pulmonary Disease ◽  
Chronic Obstructive ◽  
Mrna Levels ◽  
Differentiation Potential ◽  
Obstructive Pulmonary Disease ◽  
Stem Cell Maintenance ◽  
Cell Maintenance

Abstract Objectives: Patients with Chronic Obstructive Pulmonary Disease (COPD) have a bronchial epithelium with many anomalies and basal/progenitor cells showing a decrease of self-renewal and differentiation potential. The objective of this study was to identify deregulations in the genetic program of COPD bronchial progenitors that could account for their exhaustion. The transcription factor Slug/Snail2 is highly expressed in bronchial progenitors and we aimed at identifying genes downstream of Slug whose expression is deregulated in COPD progenitors. Results: We knocked down Slug in primary basal cells from COPD subjects and, since COPD subjects have higher levels of Transforming Growth Factor (TGF)-β Slug is regulated by TGF-β, we selected genes downstream of Slug involved in differentiation that respond to TGF-β. We identified transcription factors involved in stem cell maintenance downstream of Slug and repressed by TGF-β in COPD but not normal progenitors. We found that the effect of TGF-β on the expression of these genes is correlated to Slug knockdown effect. We also found a correlation between the mRNA levels of Slug and these genes only in presence of TGF-β. These results reveal that stem cell maintenance genes are deregulated in COPD bronchial progenitors, Slug and TGF-β being involved in that deregulation.

scholarly journals CUL1-Mediated Organelle Fission Pathway Inhibits the Development of Chronic Obstructive Pulmonary Disease

2020 ◽  
Vol 2020 ◽  
pp. 1-11
Author(s):  
Ran Li ◽  
Feng Xu ◽  
Xiao Wu ◽  
Shaoping Ji ◽  
Ruixue Xia
Keyword(s):  
Chronic Obstructive Pulmonary Disease ◽  
Transcription Factors ◽  
Pulmonary Disease ◽  
Target Genes ◽  
Enrichment Analysis ◽  
Development Trend ◽  
Chronic Obstructive ◽  
Hypergeometric Test ◽  
Obstructive Pulmonary Disease ◽  
Depth Analysis

Chronic obstructive pulmonary disease (COPD) is a global high-incidence chronic airway inflammation disease. Its deterioration will lead to more serious lung lesions and even lung cancer. Therefore, it is urgent to determine the pathogenesis of COPD and find potential therapeutic targets. The purpose of this study is to reveal the molecular mechanism of COPD disease development through in-depth analysis of transcription factors and ncRNA-driven pathogenic modules of COPD. We obtained the expression profile of COPD-related microRNAs from the NCBI-GEO database and analyzed the differences among groups to identify the microRNAs significantly associated with COPD. Then, their target genes are predicted and mapped to a protein-protein interaction (PPI) network. Finally, key transcription factors and the ncRNA of the regulatory module were identified based on the hypergeometric test. The results showed that CUL1 was the most interactive gene in the highly interactive module, so it was recognized as a dysfunctional molecule of COPD. Enrichment analysis also showed that it was much involved in the biological process of organelle fission, the highest number of regulatory modules. In addition, ncRNAs, mainly composed of miR-590-3p, miR-495-3p, miR-186-5p, and transcription factors such as MYC, BRCA1, and CDX2, significantly regulate COPD dysfunction blocks. In summary, we revealed that the COPD-related target gene CUL1 plays a key role in the potential dysfunction of the disease. It promotes the proliferation of fibroblast cells in COPD patients by mediating functional signals of organelle fission and thus participates in the progress of the disease. Our research helps biologists to further understand the etiology and development trend of COPD.

scholarly journals Human Umbilical Cord Mesenchymal Stem Cell-Derived Extracellular Vesicles Ameliorate Airway Inflammation in a Rat Model of chronic obstructive pulmonary disease (COPD)

2020 ◽  
Author(s):  
Noridzzaida Ridzuan ◽  
Norashikin Zakaria ◽  
Darius Widera ◽  
Jonathan Sheard ◽  
Mitsuru Morimoto ◽  
...  
Keyword(s):  
Chronic Obstructive Pulmonary Disease ◽  
Stem Cell ◽  
Mesenchymal Stem Cell ◽  
Pulmonary Disease ◽  
Umbilical Cord ◽  
Extracellular Vesicles ◽  
Rat Model ◽  
Chronic Obstructive ◽  
Human Umbilical Cord ◽  
Obstructive Pulmonary Disease

Abstract Background: Chronic obstructive pulmonary disease (COPD) is an incurable and debilitating chronic disease characterized by progressive airflow limitation associated with abnormal levels of tissue inflammation. Therefore, stem cell-based approaches to tackle the condition are currently a focus of regenerative therapies for COPD. Extracellular vesicles (EVs) released by all cell types are crucially involved in paracrine, extracellular communication. Recent advances in the field suggest that stem cell-derived EVs possess a therapeutic potential which is comparable to the cells of their origin.Methods: In this study, we assessed the potential anti-inflammatory effects of human umbilical cord mesenchymal stem cell (hUC-MSCs) derived EVs in a rat model of COPD. EVs were isolated from hUC-MSCs and characterized by the transmission electron microscope, western blotting, and nanoparticle tracking analysis. As a model of COPD, male Sprague Dawley rats were exposed to cigarette smoke for up to 12 weeks, followed by transplantation of hUC-MSCs or application of hUC-MSCs-derived EVs. Lung tissue was subjected to histological analysis using hematoxylin and eosin staining, alcian blue-periodic acid Schiff (AB-PAS) staining, and immunofluorescence staining. Gene expression in the lung tissue was assessed using microarray analysis. Statistical analyses were performed using GraphPad Prism 7 version 7.0 (GraphPad Software, USA). Student’s t-test was used to compare between 2 groups. Comparison among more than 2 groups was done using one-way analysis of variance (ANOVA). Data presented as median±standard deviation (SD).Results: Both, transplantation of hUC-MSCs and application of EVs resulted in a reduction of peribronchial and perivascular inflammation, alveolar septal thickening associated with mononuclear inflammation, as well as a decreased number of goblet cells. Moreover, hUC-MSCs and EVs ameliorated the loss of alveolar septa in the emphysematous lung of COPD rats and reduced the levels of NF-κB subunit p65 in the tissue. Subsequent microarray analysis revealed that both hUC-MSCs and EVs significantly regulate multiple pathways known to be associated with COPD. Conclusions: In conclusion, we show that hUC-MSCs-derived EVs effectively ameliorate by COPD-induced inflammation. Thus, EVs could serve as a new cell-free based therapy for the treatment of COPD.

scholarly journals The Strong Correlation Between ADAM33 Expression and Airway Inflammation in Chronic Obstructive Pulmonary Disease and Candidate for Biomarker and Treatment of COPD

2021 ◽  
Author(s):  
Muhammad Fachri ◽  
Mochammad Hatta ◽  
Muhammad Nasrum Massi ◽  
Arif Santoso ◽  
Tri Ariguntar Wikanningtyas ◽  
...  
Keyword(s):  
Chronic Obstructive Pulmonary Disease ◽  
Airway Inflammation ◽  
Pulmonary Disease ◽  
Univariate Analysis ◽  
Bivariate Analysis ◽  
Chronic Obstructive ◽  
Mrna Levels ◽  
Obstructive Pulmonary Disease ◽  
Copd Patients ◽  
Potential Biomarker

Abstract Airway inflammation in patients with chronic obstructive pulmonary disease (COPD) is an amplified response of the normal immune system that occurs as a result of chronic irritation by toxic substances, such as cigarette smoke. This leads to the characteristic pathological changes in the inflammatory cells of COPD patients. ADAM33 has been reported to be involved in the pathogenesis of COPD in East Asia by affecting airway inflammation and other immune responses. The aim of this study was to determine the potential role of ADAM33 (mRNA and soluble levels) as a biomarker of inflammation in COPD patients. This is a case-control study using consecutive sampling. The COPD case and control (non-COPD) groups comprised 37 and 29 patients, respectively. We used univariate analysis to assess differences in the parameters between the groups and bivariate analysis to non-parametrically compare these parameters between the two groups. We observed significantly higher mRNA levels of ADAM33 in the COPD patients (10.39 ± 1.76) as compared to that in the non-COPD individuals (6.93 ± 0.39; p < 0.001). The levels of soluble ADAM33 were also significantly higher in the COPD patients (2.188 ± 1.142 ng/ml) compared to the non-COPD individuals (0.487 ± 0.105 ng/ml; p < 0.001). The mRNA and soluble ADAM33 levels were significantly higher in COPD patients compared to those in the parameter-matched non-COPD individuals. Thus, ADAM33 is a potential biomarker and treatment for inflammation in COPD patients.

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