Early events marking lung fibroblast transition to profibrotic state in idiopathic pulmonary fibrosis
Abstract Background Idiopathic Pulmonary Fibrosis (IPF) is an age-associated progressive lung disease with accumulation of scar tissue impairing gas exchange. Previous high-throughput studies elucidated the role of cellular heterogeneity and molecular pathways in advanced disease. However, critical...
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| Format: | Article |
| Language: | English |
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BMC
2023-04-01
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| Series: | Respiratory Research |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12931-023-02419-0 |
| _version_ | 1797840887352393728 |
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| author | Minxue Jia Lorena Rosas Maria G. Kapetanaki Tracy Tabib John Sebrat Tamara Cruz Anna Bondonese Ana L. Mora Robert Lafyatis Mauricio Rojas Panayiotis V. Benos |
| author_facet | Minxue Jia Lorena Rosas Maria G. Kapetanaki Tracy Tabib John Sebrat Tamara Cruz Anna Bondonese Ana L. Mora Robert Lafyatis Mauricio Rojas Panayiotis V. Benos |
| author_sort | Minxue Jia |
| collection | DOAJ |
| description | Abstract Background Idiopathic Pulmonary Fibrosis (IPF) is an age-associated progressive lung disease with accumulation of scar tissue impairing gas exchange. Previous high-throughput studies elucidated the role of cellular heterogeneity and molecular pathways in advanced disease. However, critical pathogenic pathways occurring in the transition of fibroblasts from normal to profibrotic have been largely overlooked. Methods We used single cell transcriptomics (scRNA-seq) from lungs of healthy controls and IPF patients (lower and upper lobes). We identified fibroblast subclusters, genes and pathways associated with early disease. Immunofluorescence assays validated the role of MOXD1 early in fibrosis. Results We identified four distinct fibroblast subgroups, including one marking the normal-to-profibrotic state transition. Our results show for the first time that global downregulation of ribosomal proteins and significant upregulation of the majority of copper-binding proteins, including MOXD1, mark the IPF transition. We find no significant differences in gene expression in IPF upper and lower lobe samples, which were selected to have low and high degree of fibrosis, respectively. Conclusions Early events during IPF onset in fibroblasts include dysregulation of ribosomal and copper-binding proteins. Fibroblasts in early stage IPF may have already acquired a profibrotic phenotype while hallmarks of advanced disease, including fibroblast foci and honeycomb formation, are still not evident. The new transitional fibroblasts we discover could prove very important for studying the role of fibroblast plasticity in disease progression and help develop early diagnosis tools and therapeutic interventions targeting earlier disease states. |
| first_indexed | 2024-04-09T16:22:04Z |
| format | Article |
| id | doaj.art-dde4cdd40c214eafbea635dd5cd10002 |
| institution | Directory Open Access Journal |
| issn | 1465-993X |
| language | English |
| last_indexed | 2024-04-09T16:22:04Z |
| publishDate | 2023-04-01 |
| publisher | BMC |
| record_format | Article |
| series | Respiratory Research |
| spelling | doaj.art-dde4cdd40c214eafbea635dd5cd100022023-04-23T11:26:09ZengBMCRespiratory Research1465-993X2023-04-0124111310.1186/s12931-023-02419-0Early events marking lung fibroblast transition to profibrotic state in idiopathic pulmonary fibrosisMinxue Jia0Lorena Rosas1Maria G. Kapetanaki2Tracy Tabib3John Sebrat4Tamara Cruz5Anna Bondonese6Ana L. Mora7Robert Lafyatis8Mauricio Rojas9Panayiotis V. Benos10Department of Computational and Systems Biology, University of PittsburghDepartment of Internal Medicine, Division Pulmonary, Critical Care and Sleep Medicine, The Ohio State UniversityDepartment of Computational and Systems Biology, University of PittsburghDivision of Rheumatology and Clinical Immunology, Department of Medicine, University of Pittsburgh School of MedicineDepartment of Internal Medicine, Division Pulmonary, Critical Care and Sleep Medicine, The Ohio State UniversityDepartment of Internal Medicine, Division Pulmonary, Critical Care and Sleep Medicine, The Ohio State UniversityDepartment of Internal Medicine, Division Pulmonary, Critical Care and Sleep Medicine, The Ohio State UniversityDepartment of Internal Medicine, Division Pulmonary, Critical Care and Sleep Medicine, The Ohio State UniversityDivision of Rheumatology and Clinical Immunology, Department of Medicine, University of Pittsburgh School of MedicineDepartment of Internal Medicine, Division Pulmonary, Critical Care and Sleep Medicine, The Ohio State UniversityDepartment of Computational and Systems Biology, University of PittsburghAbstract Background Idiopathic Pulmonary Fibrosis (IPF) is an age-associated progressive lung disease with accumulation of scar tissue impairing gas exchange. Previous high-throughput studies elucidated the role of cellular heterogeneity and molecular pathways in advanced disease. However, critical pathogenic pathways occurring in the transition of fibroblasts from normal to profibrotic have been largely overlooked. Methods We used single cell transcriptomics (scRNA-seq) from lungs of healthy controls and IPF patients (lower and upper lobes). We identified fibroblast subclusters, genes and pathways associated with early disease. Immunofluorescence assays validated the role of MOXD1 early in fibrosis. Results We identified four distinct fibroblast subgroups, including one marking the normal-to-profibrotic state transition. Our results show for the first time that global downregulation of ribosomal proteins and significant upregulation of the majority of copper-binding proteins, including MOXD1, mark the IPF transition. We find no significant differences in gene expression in IPF upper and lower lobe samples, which were selected to have low and high degree of fibrosis, respectively. Conclusions Early events during IPF onset in fibroblasts include dysregulation of ribosomal and copper-binding proteins. Fibroblasts in early stage IPF may have already acquired a profibrotic phenotype while hallmarks of advanced disease, including fibroblast foci and honeycomb formation, are still not evident. The new transitional fibroblasts we discover could prove very important for studying the role of fibroblast plasticity in disease progression and help develop early diagnosis tools and therapeutic interventions targeting earlier disease states.https://doi.org/10.1186/s12931-023-02419-0Idiopathic Pulmonary FibrosisFibroblastsCopperRibosomal proteinsMOXD1scRNA-seq |
| spellingShingle | Minxue Jia Lorena Rosas Maria G. Kapetanaki Tracy Tabib John Sebrat Tamara Cruz Anna Bondonese Ana L. Mora Robert Lafyatis Mauricio Rojas Panayiotis V. Benos Early events marking lung fibroblast transition to profibrotic state in idiopathic pulmonary fibrosis Respiratory Research Idiopathic Pulmonary Fibrosis Fibroblasts Copper Ribosomal proteins MOXD1 scRNA-seq |
| title | Early events marking lung fibroblast transition to profibrotic state in idiopathic pulmonary fibrosis |
| title_full | Early events marking lung fibroblast transition to profibrotic state in idiopathic pulmonary fibrosis |
| title_fullStr | Early events marking lung fibroblast transition to profibrotic state in idiopathic pulmonary fibrosis |
| title_full_unstemmed | Early events marking lung fibroblast transition to profibrotic state in idiopathic pulmonary fibrosis |
| title_short | Early events marking lung fibroblast transition to profibrotic state in idiopathic pulmonary fibrosis |
| title_sort | early events marking lung fibroblast transition to profibrotic state in idiopathic pulmonary fibrosis |
| topic | Idiopathic Pulmonary Fibrosis Fibroblasts Copper Ribosomal proteins MOXD1 scRNA-seq |
| url | https://doi.org/10.1186/s12931-023-02419-0 |
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