Routes and mechanisms of extracellular vesicle uptake

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.

Extracellular vesicles from bone marrow‐derived mesenchymal stromal cells support ex vivo survival of human antibody secreting cells

“…Within the proteomes, we identified the presence of pathways consistent with vesicular transport and targeted uptake by recipient cells, including the clathrin-mediated and caveolin-mediated signalling pathways. Both of these pathways have been shown to play a role in the uptake of EVs by B cells and PC, consistent with EV-mediated delivery of survival factors derived from stromal cells [42,43]. …”

Exosomes as secondary inductive signals involved in kidney organogenesis

“…When judging the obtained data, it should be considered that fluorescence microscopy has its limitations in resolution in the range of 390–700 nm wavelengths [42]. This is important, since exosomes are commonly 30–120 nm in diameter.…”

“…Strikingly, continued co-culture of the exosomes with the cells increased the number of exosome-positive cells, and at the time point of 24 h, most pMM cells and all of the mK4 cells had taken up vesicles (Figure 4(c)). Thus, the UBtip-derived exosomes are competent to enter the corresponding cells, which suggests uptake mechanisms such as phagocytosis, endocytosis and macropinocytosis are involved in exosome uptake [42]. The embryonic kidney-associated models provide systems to further elucidate the type of exosome entry into the cells by applying chemicals that inhibit specific endocytic pathways involved or by using specific antibodies to inhibit receptor-ligand interactions.…”

Characterization of Trichuris muris secreted proteins and extracellular vesicles provides new insights into host–parasite communication

“…At first glance, this suggests that parasite EV uptake – at least under the tested conditions – is a cell-type-unspecific process. Results from several studies show that fluorescently labelled EVs can be taken up by different cell types, whereas other studies indicate that vesicular uptake is a highly cell-type-specific process [56]. As we do not know which intestinal cells are presented in the screened murine colonic organoids, further studies should include good host cell markers to distinguish the different cells in the heterogeneous organoid system.…”