Exhaustion of Airway Basal Progenitor Cells in Early and Established Chronic Obstructive Pulmonary Disease

Ghosh, Moumita; Miller, York E.; Nakachi, Ichiro; Kwon, Jennifer B.; Barón, Anna E.; Brantley, Alexandra E.; Merrick, Daniel T.; Franklin, Wilbur A.; Keith, Robert L.; Vandivier, R. William

doi:10.1164/rccm.201704-0667oc

Cited by 92 publications

(84 citation statements)

References 62 publications

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“…In this study, an increase in several genes associated with squamous metaplasia, namely KRT5, KRT6A, KRT13, KRT14 and SFN was observed indicating that CS plays a role in squamous differentiation. These in vitro findings are in accordance with histological (known for a long time 51 ) and expression analyses (more recent ones 52 ) of COPD patients indicating that basal cells are the first cell population affected in smokers and leading to an altered differentiation pattern and architecture of the small airway epithelium. Taken together, the model can be used to investigate the molecular mechanisms underlying the early effects of smoking on basal cell proliferation.…”

Section: Discussionsupporting

confidence: 87%

“…This may reflect the pathophysiological decline in club cells observed in COPD. The reduced club cell numbers in the airways of smokers and COPD patients, respectively 7,15 , are associated with reduced uteroglobin (SCGB1A1) serum levels, which were correlated to a decline in FEV1 (Forced Expiratory Volume in 1 Second) and COPD disease progression 14,52 . In contrast to our findings, the exposure to CSE did not show a reduction in club cell numbers 27 .…”

Section: Discussionmentioning

confidence: 99%

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Intermittent exposure to whole cigarette smoke alters the differentiation of primary small airway epithelial cells in the air-liquid interface culture

Gindele

Kiechle

Benediktus

et al. 2020

Sci Rep

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Cigarette smoke (CS) is the leading risk factor to develop COPD. Therefore, the pathologic effects of whole CS on the differentiation of primary small airway epithelial cells (SAEC) were investigated, using cells from three healthy donors and three COPD patients, cultured under ALI (air-liquid interface) conditions. The analysis of the epithelial physiology demonstrated that CS impaired barrier formation and reduced cilia beat activity. Although, COPD-derived ALI cultures preserved some features known from COPD patients, CS-induced effects were similarly pronounced in ALI cultures from patients compared to healthy controls. RNA sequencing analyses revealed the deregulation of marker genes for basal and secretory cells upon CS exposure. The comparison between gene signatures obtained from the in vitro model (CS vs. air) with a published data set from human epithelial brushes (smoker vs. nonsmoker) revealed a high degree of similarity between deregulated genes and pathways induced by CS. Taken together, whole cigarette smoke alters the differentiation of small airway basal cells in vitro. the established model showed a good translatability to the situation in vivo. Thus, the model can help to identify and test novel therapeutic approaches to restore the impaired epithelial repair mechanisms in COPD, which is still a high medical need. Chronic obstructive pulmonary disease (COPD) is the third leading cause of death worldwide and its prevalence continues to rise 1. The main risk factor to develop COPD is cigarette smoke 2,3. Smoking induces epithelial injury and this repeated injury of the epithelium triggers a pathophysiologic response, which leads to tissue remodeling of the airways that is characteristic for COPD 4,5. These changes of the small airway epithelium in COPD include: Goblet cell metaplasia 6-8 , reduced cilia function 9-13 , reduced club cell numbers 7,14,15 , basal membrane thickening 16,17 , epithelial barrier dysfunction 18-20 and squamous metaplasia 8,21-23. Furthermore, the epithelial defense mechanisms against inhaled particles and pathogens are impaired enabling sub-epithelial penetration of pathogens that increases the risk of COPD patients suffering from bacterial and viral infections and subsequent exacerbations 24-26. To address cigarette smoke (CS)-induced damage on epithelial cells in vitro, previous studies used primary epithelial cells or cell lines that were mostly exposed to cigarette smoke extract (CSE) or to whole CS. These studies demonstrate smoke effects e.g. on epithelial barrier integrity, mucus production and cilia toxicity 27-34. The majority of these studies focus on the pathophysiology of large airways, i.e. bronchial or tracheal epithelial cells.

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Section: Discussionsupporting

confidence: 87%

Section: Discussionmentioning

confidence: 99%

Intermittent exposure to whole cigarette smoke alters the differentiation of primary small airway epithelial cells in the air-liquid interface culture

Gindele

Kiechle

Benediktus

et al. 2020

Sci Rep

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“…Previous works have shown at the cellular level that bronchial basal/progenitor cells from COPD are deregulated when compared to normal, with a decrease in self-renewal and a loss in differentiation potential leading to progenitor exhaustion (5,6). Our work reveals that key transcription factors involved in stem cell maintenance, direct or indirect repressed targets of Slug, have their expression deregulated in COPD, being in particular repressed when in presence of TGF-b.…”

Section: Discussionmentioning

confidence: 52%

“…These anomalies are found all along the airway epithelium as cells keep the memory of the exposure to cigarette smoke establishing a " eld of injury", and would result from an imbalance of the fate of basal cells, the airway epithelium adult stem/progenitor cells that can self-renew and/or differentiate to repair the epithelium after injury (3,4). A decrease in the count and functional ability of basal progenitors has been reported in smokers with a higher decrease in COPD smokers, leading to a statistically signi cant difference between non-smokers and smokers-COPD that correlates with the loss of respiratory capacity (5,6).…”

Section: Introductionmentioning

confidence: 99%

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

Grange¹,

Jolly²,

Courageux

et al. 2019

Preprint

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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.

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“…Basal progenitor count, self-renewal, and multipotentiality are all reduced. COPD progenitors produce an epithelium with increased basal and mucous cells and decreased ciliated cells, replicating the COPD phenotype [ 77 ]. xi.…”

Section: Mild Cognitive Impairmentmentioning

confidence: 99%

Cognitive Impairment in Chronic Obstructive Pulmonary Disease (COPD): Possible Utility of Marine Bioactive Compounds

et al. 2018

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Chronic obstructive pulmonary disease (COPD) is characterized by long-term airflow limitation. Early-onset COPD in non-smoker subjects is ≥60 years and in the elderly is often associated with different comorbidities. Cognitive impairment is one of the most common feature in patients with COPD, and is associated with COPD severity and comorbidities. Cognitive impairment in COPD enhances the assistance requirement in different aspects of daily living, treatment adherence, and effectual self-management.This review describes various bioactive compounds of natural marine sources that modulate different targets shared by both COPD and cognitive impairment and hypothesizes a possible link between these two syndromes.

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Exhaustion of Airway Basal Progenitor Cells in Early and Established Chronic Obstructive Pulmonary Disease

Abstract: Basal progenitor dysfunction relates to the histologic and physiologic manifestations of COPD and identifies a subset that may represent an early, prediagnostic stage of COPD, indicating that progenitor exhaustion is involved in COPD pathogenesis.

Cited by 92 publications

References 62 publications

Intermittent exposure to whole cigarette smoke alters the differentiation of primary small airway epithelial cells in the air-liquid interface culture

Intermittent exposure to whole cigarette smoke alters the differentiation of primary small airway epithelial cells in the air-liquid interface culture

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

Cognitive Impairment in Chronic Obstructive Pulmonary Disease (COPD): Possible Utility of Marine Bioactive Compounds

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