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.

Microglia and astrocytes differentially endocytose exosomes facilitating alpha-Synuclein endolysosomal sorting

“…Clathrin-mediated endocytosis is the best molecularly defined pathway involved in the uptake of exosomes by numerous cells including endothelial, cardiomyocytes, placenta cells and cancer cell lines (Holder et al, 2016; Banizs et al, 2018; Eguchi et al, 2019; Costafreda et al, 2020; Wu et al, 2021). In several cases, it was reported that more than one pathway may independently and cooperatively contribute to the endocytic processes (Tian et al, 2014; Cheung et al, 2016; Kanno et al, 2020; Tabak et al, 2021; Ginini et al, 2022). Additionally, identifying the endocytic pathway involved remains a challenge due to the cross-reactive effect of pharmacological inhibitors (Dutta and Donaldson, 2012; Rennick et al, 2021).…”

“…To inhibit the pathways of phagocytosis and macropinocytosis, we used the pharmacological reagent Cytochalasin D, that disrupts actin network organization, indispensable for both endocytic pathways (Ginini, 2022). DiI-labeled brain derived exosomes were added on glial cells, in the absence or presence of Cytochalasin D (Cyto), for 6h and 24h.…”

“…Mechanisms of classical endocytosis include Clathrin-mediated endocytosis (CME), Caveolin-dependent endocytosis (CDE), Lipid Raft-mediated endocytosis, Macropinocytosis and Phagocytosis. Cumulative studies have described the endocytic pathways exosomes follow, depending on their origin and target cell (Ginini et al, 2022), though, in brain cells, the mechanism(s) mediating exosome uptake still remain elusive. Fitzner and colleagues demonstrated that oligodendroglia-derived exosomes are internalized by microglia through macropinocytosis (Fitzner et al, 2011).…”

The Role of Exosomes as Mediators of Neuroinflammation in the Pathogenesis and Treatment of Alzheimer’s Disease

“…Recently, more and more studies have focused on the enrichment of plasma exosomes into microglia ( Fitzner et al, 2011 ; Ginini et al, 2022 ; Loch-Neckel et al, 2022 ). Microglia, resident immune cells in the brain, engulf dead cells and help clear out misfolded aggregates of proteins, such as amyloid plaques in AD.…”

Regulation of Extracellular Vesicle-Mediated Immune Responses against Antigen-Specific Presentation

“…Extracellular vesicles (EVs) are lipid bilayer structures secreted by living cells and are classified into either exosomes, microvesicles (MVs), or apoptotic bodies, based on the intracellular production mechanism and size ( Figure 1 ) [ 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , …”