Routes and mechanisms of extracellular vesicle uptake - PubMed (original) (raw)

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Routes and mechanisms of extracellular vesicle uptake

Laura Ann Mulcahy et al. J Extracell Vesicles. 2014.

Abstract

Extracellular vesicles (EVs) are small vesicles released by donor cells that can be taken up by recipient cells. Despite their discovery decades ago, it has only recently become apparent that EVs play an important role in cell-to-cell communication. EVs can carry a range of nucleic acids and proteins which can have a significant impact on the phenotype of the recipient. For this phenotypic effect to occur, EVs need to fuse with target cell membranes, either directly with the plasma membrane or with the endosomal membrane after endocytic uptake. EVs are of therapeutic interest because they are deregulated in diseases such as cancer and they could be harnessed to deliver drugs to target cells. It is therefore important to understand the molecular mechanisms by which EVs are taken up into cells. This comprehensive review summarizes current knowledge of EV uptake mechanisms. Cells appear to take up EVs by a variety of endocytic pathways, including clathrin-dependent endocytosis, and clathrin-independent pathways such as caveolin-mediated uptake, macropinocytosis, phagocytosis, and lipid raft-mediated internalization. Indeed, it seems likely that a heterogeneous population of EVs may gain entry into a cell via more than one route. The uptake mechanism used by a given EV may depend on proteins and glycoproteins found on the surface of both the vesicle and the target cell. Further research is needed to understand the precise rules that underpin EV entry into cells.

Keywords: EV internalization; EV uptake; cell communication; cell–EV interaction; endocytosis; exosomes; extracellular vesicles.

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Figures

Fig. 1

Fig. 1

Pathways shown to participate in EV uptake by target cells. EVs transport signals between cells. EVs have been shown to be internalized by cells through phagocytosis, clathrin- and caveolin-mediated endocytosis. There is also evidence to support their interaction with lipid rafts resulting in EV uptake. Lipid rafts are involved in both clathrin- and caveolin-mediated endocytosis. EVs can be internalized by macropinocytosis where membrane protrusions or blebs extend from the cell, fold backwards around the EVs and enclose them into the lumen of a macropinosome; alternatively EVs are macropinocytosed after becoming caught in membrane ruffles. EVs may also deliver their protein, mRNA and miRNA cargo by fusion with the plasma membrane. Alternatively, intraluminal EVs may fuse with the endosomal limiting membrane following endocytosis to enable their EV contents to elicit a phenotypic response.

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