Central lung gene expression associates with myofibroblast features in idiopathic pulmonary fibrosis
Rationale Contribution of central lung tissues to pathogenesis of idiopathic pulmonary fibrosis (IPF) remains unknown.Objective To ascertain the relationship between cell types of IPF-central and IPF-peripheral lung explants using RNA sequencing (RNA-seq) transcriptome.Methods Biopsies of paired IPF...
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BMJ Publishing Group
2023-07-01
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| Series: | BMJ Open Respiratory Research |
| Online Access: | https://bmjopenrespres.bmj.com/content/10/1/e001391.full |
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| author | Imre Noth Yong Huang Aliya N Husain Shwu-Fan Ma Jonathan Jou Rob Guzy Catherine A Bonham Jefree J Schulte John S Kim Andrew J Barros Milena S Espindola Cory M Hogaboam Anne I Sperling |
| author_facet | Imre Noth Yong Huang Aliya N Husain Shwu-Fan Ma Jonathan Jou Rob Guzy Catherine A Bonham Jefree J Schulte John S Kim Andrew J Barros Milena S Espindola Cory M Hogaboam Anne I Sperling |
| author_sort | Imre Noth |
| collection | DOAJ |
| description | Rationale Contribution of central lung tissues to pathogenesis of idiopathic pulmonary fibrosis (IPF) remains unknown.Objective To ascertain the relationship between cell types of IPF-central and IPF-peripheral lung explants using RNA sequencing (RNA-seq) transcriptome.Methods Biopsies of paired IPF-central and IPF-peripheral along with non-IPF lungs were selected by reviewing H&E data. Criteria for differentially expressed genes (DEG) were set at false discovery rate <5% and fold change >2. Computational cell composition deconvolution was performed. Signature scores were computed for each cell type.Findings Comparison of central IPF versus non-IPF identified 1723 DEG (1522 upregulated and 201 downregulated). Sixty-two per cent (938/1522) of the mutually upregulated genes in central IPF genes were also upregulated in peripheral IPF versus non-IPF. Moreover, 85 IPF central-associated genes (CAG) were upregulated in central IPF versus both peripheral IPF and central non-IPF. IPF single-cell RNA-seq analysis revealed the highest CAG signature score in myofibroblasts and significantly correlated with a previously published activated fibroblasts signature (r=0.88, p=1.6×10−4). CAG signature scores were significantly higher in IPF than in non-IPF myofibroblasts (p=0.013). Network analysis of central-IPF genes identified a module significantly correlated with the deconvoluted proportion of myofibroblasts in central IPF and anti-correlated with inflammation foci trait in peripheral IPF. The module genes were over-represented in idiopathic pulmonary fibrosis signalling pathways.Interpretation Gene expression in central IPF lung regions demonstrates active myofibroblast features that contributes to disease progression. Further elucidation of pathological transcriptomic state of cells in the central regions of the IPF lung that are relatively spared from morphological rearrangements may provide insights into molecular changes in the IPF progression. |
| format | Article |
| id | doaj-art-8ec06459ed0948489a762ccc76c5dcd7 |
| institution | DOAJ |
| issn | 2052-4439 |
| language | English |
| publishDate | 2023-07-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | BMJ Open Respiratory Research |
| spelling | doaj-art-8ec06459ed0948489a762ccc76c5dcd72025-08-20T02:58:10ZengBMJ Publishing GroupBMJ Open Respiratory Research2052-44392023-07-0110110.1136/bmjresp-2022-001391Central lung gene expression associates with myofibroblast features in idiopathic pulmonary fibrosisImre Noth0Yong Huang1Aliya N Husain2Shwu-Fan Ma3Jonathan Jou4Rob Guzy5Catherine A Bonham6Jefree J Schulte7John S Kim8Andrew J Barros9Milena S Espindola10Cory M Hogaboam11Anne I Sperling12University of Virginia, Charlottesville, Virginia, USADepartment of Immunization Programme Planning, Guangzhou Center for Disease Control and Prevention, Guangzhou, ChinaDepartment of Pathology, University of Chicago, Chicago, Illinois, USADivision of Pulmonary & Critical Care Medicine, University of Virginia, Charlottesville, Virginia, USADepartment of Surgery, University of Illinois, Peoria, Illinois, USASection of Pulmonary & Critical Care Medicine, University of Chicago, Chicago, Illinois, USADivision of Pulmonary & Critical Care Medicine, University of Virginia, Charlottesville, Virginia, USADepartment of Pathology and Laboratory Medicine, University of Wisconsin, Madison, Wisconsin, USADivision of Pulmonary & Critical Care Medicine, University of Virginia, Charlottesville, Virginia, USADivision of Pulmonary & Critical Care Medicine, University of Virginia, Charlottesville, Virginia, USADivision of Pulmonary & Critical Care Medicine, Cedars-Sinai Medical Center, Los Angeles, California, USADivision of Pulmonary & Critical Care Medicine, Cedars-Sinai Medical Center, Los Angeles, California, USADivision of Pulmonary & Critical Care Medicine, University of Virginia, Charlottesville, Virginia, USARationale Contribution of central lung tissues to pathogenesis of idiopathic pulmonary fibrosis (IPF) remains unknown.Objective To ascertain the relationship between cell types of IPF-central and IPF-peripheral lung explants using RNA sequencing (RNA-seq) transcriptome.Methods Biopsies of paired IPF-central and IPF-peripheral along with non-IPF lungs were selected by reviewing H&E data. Criteria for differentially expressed genes (DEG) were set at false discovery rate <5% and fold change >2. Computational cell composition deconvolution was performed. Signature scores were computed for each cell type.Findings Comparison of central IPF versus non-IPF identified 1723 DEG (1522 upregulated and 201 downregulated). Sixty-two per cent (938/1522) of the mutually upregulated genes in central IPF genes were also upregulated in peripheral IPF versus non-IPF. Moreover, 85 IPF central-associated genes (CAG) were upregulated in central IPF versus both peripheral IPF and central non-IPF. IPF single-cell RNA-seq analysis revealed the highest CAG signature score in myofibroblasts and significantly correlated with a previously published activated fibroblasts signature (r=0.88, p=1.6×10−4). CAG signature scores were significantly higher in IPF than in non-IPF myofibroblasts (p=0.013). Network analysis of central-IPF genes identified a module significantly correlated with the deconvoluted proportion of myofibroblasts in central IPF and anti-correlated with inflammation foci trait in peripheral IPF. The module genes were over-represented in idiopathic pulmonary fibrosis signalling pathways.Interpretation Gene expression in central IPF lung regions demonstrates active myofibroblast features that contributes to disease progression. Further elucidation of pathological transcriptomic state of cells in the central regions of the IPF lung that are relatively spared from morphological rearrangements may provide insights into molecular changes in the IPF progression.https://bmjopenrespres.bmj.com/content/10/1/e001391.full |
| spellingShingle | Imre Noth Yong Huang Aliya N Husain Shwu-Fan Ma Jonathan Jou Rob Guzy Catherine A Bonham Jefree J Schulte John S Kim Andrew J Barros Milena S Espindola Cory M Hogaboam Anne I Sperling Central lung gene expression associates with myofibroblast features in idiopathic pulmonary fibrosis BMJ Open Respiratory Research |
| title | Central lung gene expression associates with myofibroblast features in idiopathic pulmonary fibrosis |
| title_full | Central lung gene expression associates with myofibroblast features in idiopathic pulmonary fibrosis |
| title_fullStr | Central lung gene expression associates with myofibroblast features in idiopathic pulmonary fibrosis |
| title_full_unstemmed | Central lung gene expression associates with myofibroblast features in idiopathic pulmonary fibrosis |
| title_short | Central lung gene expression associates with myofibroblast features in idiopathic pulmonary fibrosis |
| title_sort | central lung gene expression associates with myofibroblast features in idiopathic pulmonary fibrosis |
| url | https://bmjopenrespres.bmj.com/content/10/1/e001391.full |
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