Dysregulation of club cell biology in idiopathic pulmonary fibrosis

Zuo, Wu-Lin; Rostami, Mahboubeh; LeBlanc, Michelle G.; Kaner, Robert J.; O’Beirne, Sarah L.; Mezey, Jason G.; Leopold, Philip L.; Quast, Karsten; Visvanathan, Sudha; Fine, Jay S.; Thomas, Matthew; Crystal, Ronald G.

doi:10.1371/journal.pone.0237529

Cited by 27 publications

(16 citation statements)

References 39 publications

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“… 32 Abnormal distribution of club cells has been reported in IPF lungs. 7 8 22 Interestingly, recent single-cell RNA seq and RNA in situ hybridisation studies also indicated the increases in club cell signature in the parenchyma of the patients with IPF. 8 33 A recent study also suggested that progenitor SCGB1A1 niches are present in the alveolar regions and act as reservoirs for alveolar type II (ATII) epithelial cells during the injury and repair process of the lung.…”

Section: Discussionmentioning

confidence: 99%

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Inhibition of PDIA3 in club cells attenuates osteopontin production and lung fibrosis

Kumar

Elko

Bruno

et al. 2021

Thorax

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BackgroundThe role of club cells in the pathology of idiopathic pulmonary fibrosis (IPF) is not well understood. Protein disulfide isomerase A3 (PDIA3), an endoplasmic reticulum-based redox chaperone required for the functions of various fibrosis-related proteins; however, the mechanisms of action of PDIA3 in pulmonary fibrosis are not fully elucidated.ObjectivesTo examine the role of club cells and PDIA3 in the pathology of pulmonary fibrosis and the therapeutic potential of inhibition of PDIA3 in lung fibrosis.MethodsRole of PDIA3 and aberrant club cells in lung fibrosis was studied by analyses of human transcriptome dataset from Lung Genomics Research Consortium, other public resources, the specific deletion or inhibition of PDIA3 in club cells and blocking SPP1 downstream of PDIA3 in mice.ResultsPDIA3 and club cell secretory protein (SCGB1A1) signatures are upregulated in IPF compared with control patients. PDIA3 or SCGB1A1 increases also correlate with a decrease in lung function in patients with IPF. The bleomycin (BLM) model of lung fibrosis showed increases in PDIA3 in SCGB1A1 cells in the lung parenchyma. Ablation of Pdia3, specifically in SCGB1A1 cells, decreases parenchymal SCGB1A1 cells along with fibrosis in mice. The administration of a PDI inhibitor LOC14 reversed the BLM-induced parenchymal SCGB1A1 cells and fibrosis in mice. Evaluation of PDIA3 partners revealed that SPP1 is a major interactor in fibrosis. Blocking SPP1 attenuated the development of lung fibrosis in mice.ConclusionsOur study reveals a new relationship with distally localised club cells, PDIA3 and SPP1 in lung fibrosis and inhibition of PDIA3 or SPP1 attenuates lung fibrosis.

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Section: Discussionmentioning

confidence: 99%

“… 3 4 There is increasing evidence that club cells play essential roles in lung repair and found in the distal lung in IPF. 5 – 8 However, the role of these distal club cells in lung fibrosis is not well studied.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of PDIA3 in club cells attenuates osteopontin production and lung fibrosis

Kumar

Elko

Bruno

et al. 2021

Thorax

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“…Furthermore, studies have also found that Scgb1a1 expressing cells may differentiate to Type 1 pneumocytes (AT1) and Type 2 pneumocytes (AT2) cells ( Zheng et al., 2012 ). More in depth studies of pulmonary pathologies are expected to shed light on this complexity, and the particular marker expression patterns associated with the various club cell phenotypes ( Zuo et al., 2020 ).…”

Section: Introductionmentioning

confidence: 99%

Human Organotypic Airway and Lung Organoid Cells of Bronchiolar and Alveolar Differentiation Are Permissive to Infection by Influenza and SARS-CoV-2 Respiratory Virus

Ekanger

Zhou

Bohan

et al. 2022

Front. Cell. Infect. Microbiol.

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The ongoing coronavirus disease 2019 (COVID-19) pandemic has led to the initiation of unprecedented research efforts to understand the pathogenesis mediated by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). More knowledge is needed regarding the cell type-specific cytopathology and its impact on cellular tropism. Furthermore, the impact of novel SARS-CoV-2 mutations on cellular tropism, alternative routes of entry, the impact of co-infections, and virus replication kinetics along the respiratory tract remains to be explored in improved models. Most applied virology models are not well suited to address the remaining questions, as they do not recapitulate the histoarchitecture and cellular composition of human respiratory tissues. The overall aim of this work was to establish from single biopsy specimens, a human adult stem cell-derived organoid model representing the upper respiratory airways and lungs and explore the applicability of this model to study respiratory virus infection. First, we characterized the organoid model with respect to growth pattern and histoarchitecture, cellular composition, and functional characteristics. Next, in situ expression of viral entry receptors, including influenza virus-relevant sialic acids and SARS-CoV-2 entry receptor ACE2 and TMPRSS2, were confirmed in organoids of bronchiolar and alveolar differentiation. We further showed successful infection by pseudotype influenza A H7N1 and H5N1 virus, and the ability of the model to support viral replication of influenza A H7N1 virus. Finally, successful infection and replication of a clinical isolate of SARS-CoV-2 were confirmed in the organoids by TCID50 assay and immunostaining to detect intracellular SARS-CoV-2 specific nucleocapsid and dsRNA. The prominent syncytia formation in organoid tissues following SARS-CoV-2 infection mimics the findings from infected human tissues in situ. We conclude that the human organotypic model described here may be particularly useful for virology studies to evaluate regional differences in the host response to infection. The model contains the various cell types along the respiratory tract, expresses respiratory virus entry factors, and supports successful infection and replication of influenza virus and SARS-CoV-2. Thus, the model may serve as a relevant and reliable tool in virology and aid in pandemic preparedness, and efficient evaluation of antiviral strategies.

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“…In light of these findings, we review previous results from the literature on the identified cell types and DEGs related to PF; see Table 1 and Table S1 ( Supplementary Materials ). In particular, DEG-enriched cell types SCGB3A2 ( Cai and Kimura, 2015 ; Zuo et al , 2020 ), AT2 ( Parimon et al , 2020 ; Wu et al , 2020 ), MUC5B ( Peljto et al , 2013 ; Seibold et al , 2011 ; Zuo et al , 2020 ) and Basal ( Carraro et al , 2020 ; Richeldi et al , 2017 ) have been previously reported.…”

Section: Resultsmentioning

confidence: 95%

BSDE: barycenter single-cell differential expression for case–control studies

Zhang

Guo

2022

Bioinformatics

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Motivation Single-cell sequencing brings about a revolutionarily high resolution for finding differentially expressed genes by disentangling highly heterogeneous cell tissues. Yet, such analysis is so far mostly focused on comparing between different cell types from the same individual. As single-cell sequencing becomes cheaper and easier to use, an increasing number of datasets from case-control studies are becoming available, which call for new methods for identifying differential expressions between case and control individuals. Results To bridge this gap, we propose Barycenter Single-cell Differential Expression (BSDE), a nonparametric method for finding differentially expressed genes for case-control studies. Through the use of optimal transportation for aggregating distributions and computing their distances, our method overcomes the restrictive parametric assumptions imposed by standard mixed-effect-modeling approaches. Through simulations, we show that BSDE can accurately detect a variety of differential expressions while maintaining the type-I error at a prescribed level. Further, 1345 and 1568 cell type specific differentially expressed genes are identified by BSDE from datasets on pulmonary fibrosis and multiple sclerosis, among which the top findings are supported by previous results from the literature. Availability R package BSDE is freely available from doi.org/10.5281/zenodo.6332254. For real data analysis with the R package, see doi.org/10.5281/zenodo.6332566. These can also be accessed thorough GitHub at github.com/mqzhanglab/BSDE and github.com/mqzhanglab/BSDE_pipeline. The two single cell sequencing datasets can be download with UCSC cell browser from cells.ucsc.edu/?ds=ms and cells.ucsc.edu/?ds=lung-pf-control. Supplementary information Supplementary data are available at Bioinformatics online.

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Dysregulation of club cell biology in idiopathic pulmonary fibrosis

Cited by 27 publications

References 39 publications

Inhibition of PDIA3 in club cells attenuates osteopontin production and lung fibrosis

Inhibition of PDIA3 in club cells attenuates osteopontin production and lung fibrosis

Human Organotypic Airway and Lung Organoid Cells of Bronchiolar and Alveolar Differentiation Are Permissive to Infection by Influenza and SARS-CoV-2 Respiratory Virus

BSDE: barycenter single-cell differential expression for case–control studies

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