Early events marking lung fibroblast transition to profibrotic state in idiopathic pulmonary fibrosis
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Published:2023-04-21
Issue:1
Volume:24
Page:
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ISSN:1465-993X
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Container-title:Respiratory Research
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language:en
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Short-container-title:Respir Res
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.
Abstract
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.
Funder
National Heart, Lung, and Blood Institute,United States
Publisher
Springer Science and Business Media LLC
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