By showing that exosomes autonomously initiate fibronectin fibrillogenesis in a cell-free system via surface integrins and syndecan-1, this work overturns decades of cell-centric matrix dogma and reframes fibrosis and tumor stroma as exosome-driven processes.
Exosomes function as autonomous extracellular matrix assembly machines that directly induce fibronectin fibrillogenesis through surface-displayed integrins and syndecan-1, challenging the longstanding paradigm that matrix assembly requires intact cells and establishing exosome-mediated matrix remodeling as a critical driver of pathological fibrosis and cancer metastasis.
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.