Molecular mapping of interstitial lung disease reveals a phenotypically distinct senescent basal epithelial cell population
Compromised regenerative capacity of lung epithelial cells can lead to cellular senescence, which may precipitate fibrosis. While increased markers of senescence have been reported in idiopathic pulmonary fibrosis (IPF), the origin and identity of these senescent cells remain unclear, and tools to c...
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Published in | JCI insight Vol. 6; no. 8 |
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Main Authors | , , , , , , , |
Format | Journal Article |
Language | English |
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United States
American Society for Clinical Investigation
22.04.2021
American Society for Clinical investigation |
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Abstract | Compromised regenerative capacity of lung epithelial cells can lead to cellular senescence, which may precipitate fibrosis. While increased markers of senescence have been reported in idiopathic pulmonary fibrosis (IPF), the origin and identity of these senescent cells remain unclear, and tools to characterize context-specific cellular senescence in human lung are lacking. We observed that the senescent marker p16 is predominantly localized to bronchiolized epithelial structures in scarred regions of IPF and systemic sclerosis-associated interstitial lung disease (SSc-ILD) lung tissue, overlapping with the basal epithelial markers Keratin 5 and Keratin 17. Using in vitro models, we derived transcriptional signatures of senescence programming specific to different types of lung epithelial cells and interrogated these signatures in a single-cell RNA-Seq data set derived from control, IPF, and SSc-ILD lung tissue. We identified a population of basal epithelial cells defined by, and enriched for, markers of cellular senescence and identified candidate markers specific to senescent basal epithelial cells in ILD that can enable future functional studies. Notably, gene expression of these cells significantly overlaps with terminally differentiating cells in stratified epithelia, where it is driven by p53 activation as part of the senescence program. |
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AbstractList | Compromised regenerative capacity of lung epithelial cells can lead to cellular senescence, which may precipitate fibrosis. While increased markers of senescence have been reported in idiopathic pulmonary fibrosis (IPF), the origin and identity of these senescent cells remain unclear, and tools to characterize context-specific cellular senescence in human lung are lacking. We observed that the senescent marker p16 is predominantly localized to bronchiolized epithelial structures in scarred regions of IPF and systemic sclerosis–associated interstitial lung disease (SSc-ILD) lung tissue, overlapping with the basal epithelial markers Keratin 5 and Keratin 17. Using in vitro models, we derived transcriptional signatures of senescence programming specific to different types of lung epithelial cells and interrogated these signatures in a single-cell RNA-Seq data set derived from control, IPF, and SSc-ILD lung tissue. We identified a population of basal epithelial cells defined by, and enriched for, markers of cellular senescence and identified candidate markers specific to senescent basal epithelial cells in ILD that can enable future functional studies. Notably, gene expression of these cells significantly overlaps with terminally differentiating cells in stratified epithelia, where it is driven by p53 activation as part of the senescence program. |
Author | Modrusan, Zora Arron, Joseph R Heiden, Jason A Vander Wolters, Paul J DePianto, Daryle J Morshead, Katrina B Teng, Grace Sun, Kai-Hui |
AuthorAffiliation | 2 Department of OMNI Bioinformatics, and 1 Department of Immunology Discovery 3 Department of Molecular Biology, Genentech Inc., San Francisco, California, USA 4 Division of Pulmonary, Critical Care, Allergy and Sleep Medicine, Department of Medicine, University of California, San Francisco, California, USA |
AuthorAffiliation_xml | – name: 3 Department of Molecular Biology, Genentech Inc., San Francisco, California, USA – name: 1 Department of Immunology Discovery – name: 2 Department of OMNI Bioinformatics, and – name: 4 Division of Pulmonary, Critical Care, Allergy and Sleep Medicine, Department of Medicine, University of California, San Francisco, California, USA |
Author_xml | – sequence: 1 givenname: Daryle J surname: DePianto fullname: DePianto, Daryle J organization: Department of Immunology Discovery – sequence: 2 givenname: Jason A Vander surname: Heiden fullname: Heiden, Jason A Vander organization: Department of OMNI Bioinformatics, and – sequence: 3 givenname: Katrina B surname: Morshead fullname: Morshead, Katrina B organization: Department of Immunology Discovery – sequence: 4 givenname: Kai-Hui surname: Sun fullname: Sun, Kai-Hui organization: Department of Molecular Biology, Genentech Inc., San Francisco, California, USA – sequence: 5 givenname: Zora surname: Modrusan fullname: Modrusan, Zora organization: Department of Molecular Biology, Genentech Inc., San Francisco, California, USA – sequence: 6 givenname: Grace surname: Teng fullname: Teng, Grace organization: Department of Immunology Discovery – sequence: 7 givenname: Paul J surname: Wolters fullname: Wolters, Paul J organization: Division of Pulmonary, Critical Care, Allergy and Sleep Medicine, Department of Medicine, University of California, San Francisco, California, USA – sequence: 8 givenname: Joseph R surname: Arron fullname: Arron, Joseph R organization: Department of Immunology Discovery |
BackLink | https://www.ncbi.nlm.nih.gov/pubmed/33705361$$D View this record in MEDLINE/PubMed |
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Keywords | Pulmonology Aging Cellular senescence Fibrosis |
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SubjectTerms | Aged Aging Case-Control Studies Cellular Senescence - genetics Cyclin-Dependent Kinase Inhibitor p16 - metabolism Epithelial Cells - metabolism Female Humans Idiopathic Pulmonary Fibrosis - genetics Idiopathic Pulmonary Fibrosis - metabolism Idiopathic Pulmonary Fibrosis - pathology Keratin-17 - metabolism Keratin-5 - metabolism Lung Lung Diseases, Interstitial - etiology Lung Diseases, Interstitial - genetics Lung Diseases, Interstitial - metabolism Lung Diseases, Interstitial - pathology Male Middle Aged Pulmonology Respiratory Mucosa RNA-Seq Scleroderma, Systemic - complications Scleroderma, Systemic - genetics Scleroderma, Systemic - metabolism Scleroderma, Systemic - pathology Single-Cell Analysis Transcriptome Tumor Suppressor Protein p53 - genetics Tumor Suppressor Protein p53 - metabolism |
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Title | Molecular mapping of interstitial lung disease reveals a phenotypically distinct senescent basal epithelial cell population |
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