Human primary airway basal cells display a continuum of molecular phases from health to disease in COPD
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ABSTRACT:
PROVIDER: PRJNA667065 | ENA |
REPOSITORIES: ENA
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Project description:Airway basal cells are crucial for regeneration of the human lung airway epithelium, and are thought to be important contributors to chronic obstructive pulmonary disease (COPD). However, to reveal how basal cells contribute to disease, the basal cells need to be further characterized. We aimed to study primary human basal cells from healthy donors and COPD patients in order to identify key differences that could further our understanding of the disease mechanisms. In this study, we optimized a sorting protocol for primary human basal cells dependent on cell size and NGFR expression. The basal cell population was found to be heterogeneous in contrast to cultured basal cells. In addition, significant differences such as KRT14 expression was found exclusively in cultured cells. Also, colony-forming capacity was significantly increased in cultured cells showing a clonal enrichment in vitro. Next, by single cell RNA sequencing on primary basal cells from healthy donors and COPD patients, the gene expression changes revealed a continuum ranging from healthy basal cell signatures to diseased basal cells phenotypes. We identified several upregulated genes that may be indicative of COPD, such as stress response related genes GADD45B and AHSA1, along with genes involved in the response to hypoxia such as CITED2 and SOD1. Taken together, the presence of both healthy and diseased basal cells in stage IV COPD demonstrates the potential for regeneration through the discovery of novel therapeutic targets. In addition, we show the importance of studying primary basal cells when investigating disease mechanisms in the human lung.
2021-03-01 | GSE158942 | GEO
Project description:Continuous stress caused by smoking induces changes in the cell population of small airway epithelium, with basal cell hyperplasia and goblet cell metaplasia at the expense of ciliated cells, and there is now compiling evidence that basal cells play a key role in the early pathogenesis of Chronic Obtructive Pulmonary Disease (COPD). We hypothesized that COPD airway basal cells undergo transcriptomic changes during differentiation that are different from those observed in normal cells and can explain the formation of an abnormal epithelium. We performed microarray analysis of basal cells obtained from healthy non-smoker and COPD subjects and also mucociliary-differentiated cell cultures from the same basal cells. We compared the transcriptome of normal and COPD basal cells, mucociliary-differentiated normal and COPD cell cultures and also of basal cells with corresponding mucociliary-differentiated cultures for both normal and COPD.
2020-10-31 | GSE137557 | GEO
Project description:Activated eosinophils is a major cell type to be mainly involved in allergic diseases. Recent studies also indicated that eosinophils play an important role in the pathogenesis of chronic obstructive pulmonary disease (COPD), especially asthma-COPD overlap and/or eosinophil COPD. The aim of this study is to clarify cellular characters of human eosinophils in patients with asthma-COPD overlap and/or eosinophil COPD.
2024-06-20 | PXD052550 | JPOST Repository
Project description:Chronic obstructive pulmonary disease (COPD) is a highly prevalent disease leading to irreversible airflow limitation and is characterized by chronic pulmonary inflammation，obstructive bronchiolitis and emphysema. Etiologically, COPD is mediated by toxic gases and particles, e.g. cigarette smoke, while the pathogenesis of the disease is largely unknown. Several lines of evidence indicate a link between COPD and autoimmunity but comprehensive studies are lacking. By using a protein microarray assaying more than 19,000 human proteins we determined in this study the autoantibody profiles of COPD and non-COPD smokers.
2019-06-21 | GSE133096 | GEO
Project description:Rationale: COPD (Chronic Obstructive Pulmonary Disease) is a disease characterized by persistent airway inflammation and disordered macrophage function. The extent to which alterations in macrophage bioenergetics contribute to impaired antioxidant responses and disease pathogenesis has yet to be fully delineated. Objectives: Through the study of COPD alveolar (AM) and peripheral monocyte-derived (MDM) macrophages, we sought to establish if intrinsic defects in core metabolic processes drive macrophage dysfunction and redox imbalance. Methods: AM and MDM from COPD and healthy donors underwent functional, metabolic and transcriptional profiling. Results: We observe that AM and MDM from COPD donors display a critical depletion in glycolytic and mitochondrial respiration derived energy reserves and an over reliance on glycolysis as a source for ATP, resulting in reduced energy status. Defects in oxidative metabolism extend to an impaired redox balance associated with defective expression of the NADPH generating enzyme, malic enzyme 1, a known target of the anti-oxidant transcription factor NRF2. Consequently, selective activation of NRF2 resets the COPD transcriptome, resulting in increased generation of TCA cycle intermediaries, improved energetic status, favorable redox balance and a recovery of macrophage function. Conclusion: In COPD an inherent loss of metabolic plasticity leads to metabolic exhaustion and reduced redox capacity which can be rescued by activation of the NRF2 pathway. Targeting these defects, via NRF2 augmentation, may therefore present an attractive therapeutic strategy for the treatment of the aberrant airway inflammation described in COPD.
2023-04-02 | PXD040504 | Pride
Project description:Introduction: Environmental pollutants irritate and injure the bronchial elevator, thereby provoking disease progression in chronic obstructive pulmonary disease (COPD). Epithelial resilience mechanisms to environmental nanoparticles in health and disease are poorly characterized. Methods: We delineated the impact of prevalent pollutants such as carbon and zinc oxide nanoparticles, on cellular function and progeny in primary human bronchial epithelial cells (pHBEC) from end-stage COPD, early disease and pulmonary healthy individuals. After nanoparticle exposure of pHBECs at the air liquid interface, cell cultures were characterized by functional assays as well as transcriptome and protein analysis, complemented by single cell analysis in serial samples of pHBEC culture focussing on basal cell differentiation. Results: In end-stage COPD, environmentally abundant doses of zinc oxide nanoparticles (ZnO) aggravated a pro-secretory phenotype at the expense of the multi-ciliated epithelium alongside a reduction of barrier integrity and increased resilience towards cell damage. Similar effects on cellular composition and function were induced by co-treatment of early stage COPD pHEBC cultures with cigarette smoke extract. Time-resolved single cell transcriptomics revealed a unique end stage COPD associated basal cell state characterized by altered Wnt and Notch pathway activation. A conserved set of COPD specific genes persisted from this disease associated basal cell state into its differentiated progeny. Conclusion: We identified COPD stage specific gene program alterations in basal stem cells that affect the cellular composition of the bronchial elevator and may control epithelial resilience mechanisms in response to environmental nanoparticles. The identified phenomena likely inform treatment or prevention strategies.
2024-01-06 | GSE208662 | GEO
Project description:Rationale: Genome-wide association studies (GWAS) and candidate gene studies have identified a number of loci linked to susceptibility of chronic obstructive pulmonary disease (COPD), a smoking-related disorder that originates in the airway epithelium. Objectives: Since airway basal cell (BC) stem/progenitor cells exhibit the earliest abnormalities associated with smoking (hyperplasia, squamous metaplasia), we hypothesized that smoker BC have a dysregulated transcriptome linked, in part, to known GWAS/candidate gene loci. Methods: Massive parallel RNA sequencing was used to compare the transcriptome of BC purified from the airway epithelium of healthy nonsmokers (n=10) and smokers (n=7). The chromosomal location of the differentially expressed genes was compared to loci identified by GWAS and candidate gene studies to confer risk for COPD. Measurements and Main Results: Smoker BC have 676 known genes differentially expressed compared to nonsmoker BC, dominated by smoking up-regulation. Strikingly, 166 (25%) of these genes are located on chromosome 19, with 13 localized to 19q13.2 (p<10-4 compared to chance), including TGFB1, LTBP4, EGLN2 and NFKBIB, genes associated with risk for COPD. Conclusions: These observations provide the first direct link of known genetic risks for smoking-related lung disease with the specific population of lung cells that undergoes the earliest changes associated with smoking.
2014-05-08 | GSE47718 | GEO
Project description:Rationale: Genome-wide association studies (GWAS) and candidate gene studies have identified a number of loci linked to susceptibility of chronic obstructive pulmonary disease (COPD), a smoking-related disorder that originates in the airway epithelium. Objectives: Since airway basal cell (BC) stem/progenitor cells exhibit the earliest abnormalities associated with smoking (hyperplasia, squamous metaplasia), we hypothesized that smoker BC have a dysregulated transcriptome linked, in part, to known GWAS/candidate gene loci. Methods: Massive parallel RNA sequencing was used to compare the transcriptome of BC purified from the airway epithelium of healthy nonsmokers (n=10) and smokers (n=7). The chromosomal location of the differentially expressed genes was compared to loci identified by GWAS and candidate gene studies to confer risk for COPD. Measurements and Main Results: Smoker BC have 676 known genes differentially expressed compared to nonsmoker BC, dominated by smoking up-regulation. Strikingly, 166 (25%) of these genes are located on chromosome 19, with 13 localized to 19q13.2 (p<10-4 compared to chance), including TGFB1, LTBP4, EGLN2 and NFKBIB, genes associated with risk for COPD. Conclusions: These observations provide the first direct link of known genetic risks for smoking-related lung disease with the specific population of lung cells that undergoes the earliest changes associated with smoking. The human airway basal cell transcriptome of 7 smokers versus 10 nonsmokers was compared using massive parallel RNA sequencing (Illumina HiSeq 2000).
2014-05-08 | E-GEOD-47718 | biostudies-arrayexpress
Project description:To study the effects of treatment with an inhaled PI3Kδ inhibitor during recovery from an exacerbation of Chronic Obstructive Pulmonary Disease (COPD) due to corrective effects on neutrophils that display dysregulated migration characteristics. We aimed to develop novel induced sputum endpoints to demonstrate changes in neutrophil phenotype and proof of mechanism of action in the lung.
2020-12-31 | GSE148877 | GEO
Project description:To study the effects of treatment with an inhaled PI3Kδ inhibitor during recovery from an exacerbation of Chronic Obstructive Pulmonary Disease (COPD) due to corrective effects on neutrophils that display dysregulated migration characteristics. We aimed to develop novel induced sputum endpoints to demonstrate changes in neutrophil phenotype and proof of mechanism of action in the lung.
2020-12-31 | GSE148871 | GEO