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Am J Respir Cell Mol Biol. 2018 Oct 15. doi: 10.1165/rcmb.2018-0062OC. [Epub ahead of print]

Fibronectin on the Surface of Extracellular Vesicles Mediates Fibroblast Invasion.

Author information

1
University of Alabama at Birmingham, Medicine, Birmingham, Alabama, United States.
2
UAB, Birmingham, Alabama, United States.
3
University of Alabama at Birmingham, Birmingham, Alabama, United States.
4
University of Alabama at Birmingham, Medicine / Pulmonary and Critical Care, Birmingham, Alabama, United States.
5
UAB Comprehensive Cancer Center, 66587, Surgery, Birmingham, Alabama, United States.
6
University of Alabama at Birmingham, Medicine / Pulmonary and Critical Care, Birmingham, Alabama, United States ; vthannickal@uabmc.edu.

Abstract

Extracellular vesicles (EVs) are endosome and plasma membrane-derived nanosized vesicles that participate in intercellular signaling. Although EV cargo may signal via multiple mechanisms, how signaling components on the surface of EVs mediate cellular signaling is less well understood. In this study, we show that fibroblast-derived EVs carry fibronectin on the vesicular surface, as evidenced by mass spectrometry-based proteomics (sequential windowed acquisition of all theoretical peptides; SWATH) and flow cytometric analyses. Fibroblasts undergoing replicative senescence or TGF-β1-induced senescence and fibroblasts isolated from human subjects with an age-related lung disorder, idiopathic pulmonary fibrosis, secrete higher numbers of EVs than their respective controls. Fibroblast-derived EVs induce an invasive phenotype in recipient fibroblasts. This invasive fibroblast phenotype is dependent on EV surface localization of fibronectin, interaction with the fibronectin receptor α5β1 integrin, and the activation of invasion-associated signaling pathways involving focal adhesion kinase (FAK) and Src family kinases. EVs in the cellular supernatant, unbound to the extracellular matrix, were capable of mediating invasion signaling on recipient fibroblasts, supporting a direct interaction of EV surface fibronectin with the plasma membrane of recipient cells. Together, these studies uncover a novel mechanism of EV signaling of fibroblast invasion which may be relevant in the pathogenesis of fibrotic diseases and cancer.

KEYWORDS:

Extracellular vesicles, exosomes, extracellular matrix, fibronectin, fibroblast, invasion, idiopathic pulmonary fibrosis, cancer

PMID:
30321056
DOI:
10.1165/rcmb.2018-0062OC

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