Breast cancer cell-derived extracellular vesicles accelerate collagen fibrillogenesis and integrate into the matrix

Abstract

Extracellular vesicle (EV) and nanoparticle interactions with extracellular matrix (ECM) environments are often studied through a paradigm whereby particles are a passive element whose diffusion and behaviour are subject to the composition and structure of the environment they are in. While EV diffusion and distribution in tissues are indeed governed by matrix interactions, accumulating evidence suggests that EVs contain much of the cellular machinery required for actively remodeling ECM as well. Using rheology and confocal reflectance microscopy to investigate the gelation of collagen I hydrogels formed in the presence of EVs, we show that EVs can play an active role in the formation of new ECM. EVs appear to nucleate new fibrils, recruiting collagen molecules from solution and accelerating their polymerization. Trypsinization of EVs to digest their surface proteins shows that proteins are primarily responsible for this phenomenon. The use of extruded plasma membrane vesicles shows that membrane composition plays an important role in determining final fibril length and matrix structure. EVs also become integrated into the fibril structures that they help form, reminiscent of matrix vesicles found in situ within tissues. This represents a plausible way by which EVs are deposited into the extracellular environment, becoming important contextual signaling cues for resident cells. Our data show that EV-matrix interactions are dynamic and reciprocal, contributing to the remodeling of tissue microenvironments.