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Publications

Journal Article Preprint Epublish

PubMed: 40667058 DOI: 10.1101/2025.06.23.661091

Exosomes are specialized vehicles to induce fibronectin assembly.

bioRxiv

Authors: Bong Hwan Sung, Merlyn Emmanuel, Metti K Gari, Jorge F Guerrero, Maria Virumbrales-Muñoz, David Inman, Evan Krystofiak, Alan C Rapraeger, Suzanne M Ponik, Alissa M Weaver

Affiliations

  • Department of Cell and Developmental Biology, Vanderbilt University School of Medicine.
  • Vanderbilt Center for Extracellular Vesicle Research.
  • Department of Cell and Developmental Biology, Vanderbilt University School of Medicine. Vanderbilt Center for Extracellular Vesicle Research.
  • Department of Cell and Regenerative Biology, University of Wisconsin-Madison School of Medicine and Public Health.
  • McArdle Laboratory for Cancer Research, University of Wisconsin-Madison School of Medicine and Public Health.
  • Department of Obstetrics and Gynecology, University of Wisconsin-Madison School of Medicine and Public Health.
  • Carbone Cancer Center, University of Wisconsin-Madison School of Medicine and Public Health.
  • Cell Imaging Shared Resource, Vanderbilt University School of Medicine.
  • Department of Human Oncology, University of Wisconsin-Madison School of Medicine and Public Health.
  • Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center.

Abstract

Fibronectin is a key stromal matrix molecule whose assembly into fibrils is thought to require cells. In contrast, we find that small exosome-type extracellular vesicles (EVs) are critical initiators of fibronectin assembly. Fibroblasts engineered to be deficient in exosome secretion showed greatly reduced assembly of fibronectin and other stromal matrix molecules in 2D, 3D, and in vivo environments, and led to reduced tumor growth and lung metastasis by breast cancer cells. Furthermore, transgenic mice with defects in exosome secretion had greatly reduced lung fibrosis after treatment with bleomycin. In a direct test of exosome function, we find that the addition of purified small EVs to purified soluble fibronectin in a cell-free system is sufficient to induce fibronectin assembly. The EV-induced fibronectin assembly requires the presence of fibronectin-binding integrins and Syndecan-1 in the EVs. We propose a new model in which secreted exosomes directly drive stromal matrix assembly and tissue fibrosis.

MeSH

Cells, Lung, Fibrosis, Neoplasms, Exosomes, Fibronectins