Insight into Extracellular Vesicle-Cell Communication: From Cell Recognition to Intracellular Fate

Abstract

Extracellular vesicles (EVs) are heterogamous lipid bilayer-enclosed membranous structures secreted by cells. They are comprised of apoptotic bodies, microvesicles, and exosomes, and carry a range of nucleic acids and proteins that are necessary for cell-to-cell communication via interaction on the cells surface. They initiate intracellular signaling pathways or the transference of cargo molecules, which elicit pleiotropic responses in recipient cells in physiological processes, as well as pathological processes, such as cancer. It is therefore important to understand the molecular means by which EVs are taken up into cells. Accordingly, this review summarizes the underlying mechanisms involved in EV targeting and uptake. The primary method of entry by EVs appears to be endocytosis, where clathrin-mediated, caveolae-dependent, macropinocytotic, phagocytotic, and lipid raft-mediated uptake have been variously described as being prevalent. EV uptake mechanisms may depend on proteins and lipids found on the surfaces of both vesicles and target cells. As EVs have been shown to contribute to cancer growth and progression, further exploration and targeting of the gateways utilized by EVs to internalize into tumor cells may assist in the prevention or deceleration of cancer pathogenesis.

Keywords: endocytosis; exosomes; extracellular vesicles (EVs); lipids; proteins.

Figure 1

Extracellular vesicle (EV) internalization pathways into recipient cells. Exogenous EVs have been shown to be internalized by cells via multiple endocytic pathways depending on cell type. These pathways include the following: 1-phagocytosis, a process used by professional phagocytic cells that involves the engulfment and digestion of extracellular material into plasma membrane-derived vacuoles called phagosomes; 2-macropinocytosis, a process during which the cell extends large membrane ruffles that fold back onto the cell surface and fuse to form pockets; 3-clathrin-mediated endocytosis, a process that requires interactions between ligands on the EV surface and specific receptors present on the plasma membrane which subsequently results in EV-packed clathrin-coated vesicles; 4-caveolae-dependent endocytosis, a process that is characterized by flask/cave-like invaginations marked by the presence of caveolin-1 and 5-lipid raft-mediated endocytosis, which takes place in a cholesterol- and sphingolipid-enriched microdomain that is regulated by various molecules. Internalization via different endocytotic pathways will target exogenous EVs in the endosomal compartment. EVs may also enter cells via fusion with the plasma membrane to deliver their contents.