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Early events marking lung fibroblast transition to profibrotic state in idiopathic pulmonary fibrosis

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 pathogen...

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Autores principales: Jia, Minxue, Rosas, Lorena, Kapetanaki, Maria G., Tabib, Tracy, Sebrat, John, Cruz, Tamara, Bondonese, Anna, Mora, Ana L., Lafyatis, Robert, Rojas, Mauricio, Benos, Panayiotis V.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10122312/
https://www.ncbi.nlm.nih.gov/pubmed/37085855
http://dx.doi.org/10.1186/s12931-023-02419-0
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author Jia, Minxue
Rosas, Lorena
Kapetanaki, Maria G.
Tabib, Tracy
Sebrat, John
Cruz, Tamara
Bondonese, Anna
Mora, Ana L.
Lafyatis, Robert
Rojas, Mauricio
Benos, Panayiotis V.
author_facet Jia, Minxue
Rosas, Lorena
Kapetanaki, Maria G.
Tabib, Tracy
Sebrat, John
Cruz, Tamara
Bondonese, Anna
Mora, Ana L.
Lafyatis, Robert
Rojas, Mauricio
Benos, Panayiotis V.
author_sort Jia, Minxue
collection PubMed
description 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. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12931-023-02419-0.
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spelling pubmed-101223122023-04-23 Early events marking lung fibroblast transition to profibrotic state in idiopathic pulmonary fibrosis Jia, Minxue Rosas, Lorena Kapetanaki, Maria G. Tabib, Tracy Sebrat, John Cruz, Tamara Bondonese, Anna Mora, Ana L. Lafyatis, Robert Rojas, Mauricio Benos, Panayiotis V. Respir Res Research 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. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12931-023-02419-0. BioMed Central 2023-04-21 2023 /pmc/articles/PMC10122312/ /pubmed/37085855 http://dx.doi.org/10.1186/s12931-023-02419-0 Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
spellingShingle Research
Jia, Minxue
Rosas, Lorena
Kapetanaki, Maria G.
Tabib, Tracy
Sebrat, John
Cruz, Tamara
Bondonese, Anna
Mora, Ana L.
Lafyatis, Robert
Rojas, Mauricio
Benos, Panayiotis V.
Early events marking lung fibroblast transition to profibrotic state in idiopathic pulmonary fibrosis
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 Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10122312/
https://www.ncbi.nlm.nih.gov/pubmed/37085855
http://dx.doi.org/10.1186/s12931-023-02419-0
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