Extracellular Vesicles: Interplay with the Extracellular Matrix and Modulated Cell Responses

Abstract

The discovery that cells secrete extracellular vesicles (EVs), which carry a variety of regulatory proteins, nucleic acids, and lipids, has shed light on the sophisticated manner by which cells can communicate and accordingly function. The bioactivity of EVs is not only defined by their internal content, but also through their surface associated molecules, and the linked downstream signaling effects they elicit in target cells. The extracellular matrix (ECM) contains signaling and structural molecules that are central to tissue maintenance and repair. Recently, a subset of EVs residing within the extracellular matrix has been identified. Although some roles have been proposed for matrix-bound vesicles, their role as signaling molecules within the ECM is yet to be explored. Given the close association of EVs and the ECM, it is not surprising that EVs partly mediate repair and regeneration by modulating matrix deposition and degradation through their cellular targets. This review addresses unique EV features that allow them to interact with and navigate through the ECM, describes how their release and content is influenced by the ECM, and emphasizes the emerging role of stem-cell derived EVs in tissue repair and regeneration through their matrix-modulating properties.

Keywords: exosomes; extracellular matrix; extracellular vesicles; matrix-bound vesicles; mesenchymal stem cells; microvesicles; tissue repair; wound healing.

Figure 1

Extracellular Vesicle biogenesis and features. (A) Microvesicles or ectosomes form via outward budding of the plasma membrane, pearling, and subsequent scission. (1) Endocytosis of extracellular components results in the formation of an early sorting endosome. Extracellular matrix proteins such as syndecan and other transmembrane proteins such as MT1-MMP can also be endocytosed, and subsequently associate with forming intraluminal vesicles [27]. The early endosome (2) then matures into a late sorting endosome that exchanges its cargo with intracellular constituents such as the trans-Golgi network and the endoplasmic reticulum. (3) The involution of the membrane of the endosome (late sorting endosome) results in the formation of intraluminal vesicles. A multivesicular body with multiple intraluminal vesicles faces three fates: (4) starvation, followed by fusion with autophagosome, fusion with lysosomes, or (4)* docking onto the plasma membrane and fusing to release contents as exosomes. Following their release, EVs traverse the ECM to interact with target cells or are transported in biological fluids. EV-target-cell interactions take place through various mechanisms. Entry of intact exosomes can occur via receptor-mediated endocytosis, phagocytosis, micropinocytosis, clathrin-mediated entry, caveolae, or lipid-raft-mediated endocytosis [3,28]. Alternatively, exosomes can fuse directly with their target cells, or mediate intracellular signaling by direct-receptor binding. After they interact with target cells, EVs can mediate therapeutic effects that involve ECM protein regulation. Common exosomal markers and EV properties are outlined in (B), along with EV components that interact with the ECM. Proposed EV MSC markers are outlined [29]. There is a subpopulation of EVs within the ECM (MBVs). MBVs are enriched in actin and cardiolipin, but it is not clear whether they are enriched in other common exosomal or microvesicle markers such as Annexin A1 [30]. As depicted in (C), MBVs do not express key exosomal markers; these absent markers are struck out with a line. The figure is adapted from [3,9,21]. MT1-MMP: Membrane-type matrix metalloproteinase; EVs: Extracellular vesicles; ECM: Extracellular matrix; MSC: Mesenchymal stem cell; MBVs: Matrix-bound vesicles.