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Burgy, O.* ; Mayr, C.H.* ; Schenesse, D.* ; Fousekis Papakonstantinou, E.* ; Ballester, B. ; Sengupta, A. ; She, Y.* ; Hu, Q.* ; Melo-Narváez, M.C ; Jain, E. ; Pestoni, J. ; Mozurak, M.* ; Estrada-Bernal, A.* ; Onwuka, U.* ; Coughlan, C.* ; Parimon, T.* ; Chen, P.* ; Heimerl, T.* ; Bange, G.* ; Schmeck, B.T.* ; Lindner, M. ; Hilgendorff, A. ; Ruppert, C.* ; Guenther, A.* ; Mann, M.* ; Yildirim, A.Ö. ; Eickelberg, O.* ; Jung, A.L.* ; Schiller, H. ; Lehmann, M. ; Burgstaller, G. ; Königshoff, M.*

Fibroblast-derived extracellular vesicles contain SFRP1 and mediate pulmonary fibrosis.

JCI insight 9:e168889 (2024)
Publ. Version/Full Text DOI PMC
Open Access Gold
Creative Commons Lizenzvertrag
Idiopathic pulmonary fibrosis (IPF) is a lethal chronic lung disease characterized by aberrant intercellular communication, extracellular matrix deposition, and destruction of functional lung tissue. While extracellular vesicles (EVs) accumulate in the IPF lung, their cargo and biological effects remain unclear. We interrogated the proteome of EV and non-EV fractions during pulmonary fibrosis and characterized their contribution to fibrosis. EVs accumulated 14 days after bleomycin challenge, correlating with decreased lung function and initiated fibrogenesis in healthy precision-cut lung slices. Label-free proteomics of bronchoalveolar lavage fluid EVs (BALF-EVs) collected from mice challenged with bleomycin or control identified 107 proteins enriched in fibrotic vesicles. Multiomic analysis revealed fibroblasts as a major cellular source of BALF-EV cargo, which was enriched in secreted frizzled related protein 1 (SFRP1). Sfrp1 deficiency inhibited the activity of fibroblast-derived EVs to potentiate lung fibrosis in vivo. SFRP1 led to increased transitional cell markers, such as keratin 8, and WNT/β-catenin signaling in primary alveolar type 2 cells. SFRP1 was expressed within the IPF lung and localized at the surface of EVs from patient-derived fibroblasts and BALF. Our work reveals altered EV protein cargo in fibrotic EVs promoting fibrogenesis and identifies fibroblast-derived vesicular SFRP1 as a fibrotic mediator and potential therapeutic target for IPF.
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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords Cell Biology ; Fibrosis ; Molecular Biology ; Pulmonology; Exosomes; Pathogenesis; Progenitors; Mechanisms; Responses; Release
ISSN (print) / ISBN 2379-3708
e-ISSN 2379-3708
Journal JCI insight
Quellenangaben Volume: 9, Issue: 18, Pages: , Article Number: e168889 Supplement: ,
Publisher Clarivate
Publishing Place Ann Arbor, Michigan
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Lung Health and Immunity (LHI)
Institute of Lung Biology (LHI)
Grants Technology Enhancing Cognition and Health Geriatric Research Education and Clinical Center at the VA Pittsburgh Healthcare System, Pittsburgh, Pennsylvania, USA
European Molecular Biology Organization (ERS/EMBO Joint Research Fellowship)
ERS
European Union
French National Research Agency (ANR)
NIH
DZL
Deutsche Forschungsgemeinschaft (DFG, German Research Foundation)
Von Behring Roentgen Foundation
Helmholtz Association
European Respiratory Society