Fibroblast-derived extracellular vesicles contain SFRP1 and mediate pulmonary fibrosis
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.
Authors
- Herbert B. Schiller (ORCID: https://orcid.org/0000-0001-9498-7034)
- Anne Hilgendorff (ORCID: https://orcid.org/0000-0002-3725-996X)
- Oliver Eickelberg (ORCID: https://orcid.org/0000-0001-7170-0360)
- Tanyalak Parimon (ORCID: https://orcid.org/0000-0002-4790-0730)
- Christina Coughlan (ORCID: https://orcid.org/0000-0002-7229-7056)
- Anna Lena Jung (ORCID: https://orcid.org/0000-0002-7762-4597)
- M. Camila Melo-Narváez (ORCID: https://orcid.org/0000-0002-6067-3229)
- Thomas Heimerl
- Adriana Estrada‐Bernal (ORCID: https://orcid.org/0000-0002-0555-2766)
- Mareike Lehmann (ORCID: https://orcid.org/0000-0002-8601-8206)
- Michael Lindner (ORCID: https://orcid.org/0000-0002-2106-0286)
- Q. Hu
- Clemens Ruppert (ORCID: https://orcid.org/0000-0002-0938-2469)
- Gert Bange (ORCID: https://orcid.org/0000-0002-7826-0932)
- Jeanine C. Pestoni
- Olivier Burgy (ORCID: https://orcid.org/0000-0002-5833-3495)
- Bernd Schmeck (ORCID: https://orcid.org/0000-0002-2767-3606)
- Beatriz Ballester (ORCID: https://orcid.org/0000-0003-3059-6426)
- Yixin She
- Christoph H. Mayr (ORCID: https://orcid.org/0000-0001-5353-4768)
- Déborah Schenesse
- Arunima Sengupta (ORCID: https://orcid.org/0000-0002-0014-3242)
- Mélanie Königshoff (ORCID: https://orcid.org/0000-0001-9414-5128)
- Gerald Burgstaller (ORCID: https://orcid.org/0000-0002-7121-2567)
- Ali Önder Yildirim (ORCID: https://orcid.org/0000-0003-1969-480X)
- Matthias Mann (ORCID: https://orcid.org/0000-0003-1292-4799)
- Peter Chen (ORCID: https://orcid.org/0000-0002-5330-1718)
- Andreas Güenther (ORCID: https://orcid.org/0000-0002-2187-0975)
- Molly Mozurak
- Ugochi Onwuka
- Eshita Jain
- Efthymios Fousekis Papakonstantinou
Institutions
- Cedars-Sinai Medical Center (US)
- Inserm (FR)
- Philipps University of Marburg (DE)
- University of Pittsburgh (US)
- Université de Bourgogne (FR)
- Justus-Liebig-Universität Gießen (DE)
- Paracelsus Medical University (AT)
- Universidad Cardenal Herrera CEU (ES)
- Helmholtz Zentrum München (DE)
- Geriatric Research Education and Clinical Center (US)
- German Center for Lung Research (DE)
- Universities of Giessen and Marburg Lung Center (DE)
- VA Pittsburgh Healthcare System (US)
- Maison des Sciences sociales et des Humanités de Dijon (FR)
- Loewe Center for Synthetic Microbiology (DE)
- Max Planck Institute of Biochemistry (DE)
- Ludwig-Maximilians-Universität München (DE)
- University of Colorado Denver (US)
Publication Details
- Journal
- JCI Insight
- Published
- 2024-08-15
- DOI
- https://doi.org/10.1172/jci.insight.168889
- Citations
- 27
- Primary Topic
- Extracellular vesicles in disease
- Type
- article
- Field-Weighted Citation Impact
- 6.31
Funders
- Agence Nationale de la Recherche