Abstract
The activation and accumulation of lung fibroblasts, leading to excessive ECM deposition, is a pathogenic hallmark of Idiopathic Pulmonary Fibrosis, a lethal and currently untreatable disease. In this report, increased expression of Versican, a multifunctional ECM proteoglycan, is detected in both human and mouse pulmonary fibrosis, mainly in monocytic cells and fibroblasts. Ubiquitous genetic reduction of Versican expression in mice promotes collagen expression and polymerisation, alters pulmonary ECM composition and structure, and exacerbates pulmonary fibrosis, delaying its resolution. Moreover, the decrease in Versican in the ECM and the ensuing reorganisation stimulate Tenascin-C expression from fibroblasts, which is further shown to be a potent Toll-like receptor 4-dependent podosome inducer, promoting ECM invasion. Thus, fibroblast-expressed Versican regulates the underlying ECM composition and structure and suppresses autologous podosome formation, limiting ECM invasion and pulmonary fibrosis.
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The scRNA-seq data utilised in this study are listed in Supplementary Table 2, including accession numbers and hyperlinks. The raw MS proteomics data generated in this study have been deposited in the ProteomeXchange Consortium via the PRIDE92 partner repository under the dataset identifiers PXD060583 and PXD063546. Source data are provided with this paper.
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Acknowledgements
This research was funded by the Hellenic Foundation for Research and Innovation (HFRI) under the “2nd Call for HFRI Research Projects to support Faculty Members & Researchers” (#3565 to V.A.). S.H., I.T., and V.G. were supported by an HFRI grant (#2906 to V.G.) under the “1st Call for HFRI Research Projects to support Faculty members and Researchers and the procurement of high-cost research equipment”. The funders had no role in the study’s design, data collection, analysis, or interpretation, nor in the writing of the manuscript or the decision to publish the results.
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V.A. conceptualised, supervised and funded the study. P.K. performed most of the experiments presented, assisted by I.B., E.K., D.N., S.S., M.S., and C.M. A.G. and S.G. performed FACS analyses. V.R. performed and analysed μCT. D.F. analysed transcriptomics data. M.Sa. performed and analysed MS proteomics. A.M.B. and N.G. performed and analysed AFM and F-actin image analysis. I.T., S.H., and V.G. performed and analysed TEM. I.T. and I.V. provided human lung samples and analysed related IHC. H.W. provided resources and co-evaluated results. P.K. and V.A. wrote the manuscript, which was then critically read and edited by all authors.
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Kanellopoulou, P., Barbayianni, I., Fanidis, D. et al. Versican expression from lung fibroblasts suppresses pulmonary fibrosis. Nat Commun (2026). https://doi.org/10.1038/s41467-026-68377-5
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DOI: https://doi.org/10.1038/s41467-026-68377-5
