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Review
. 2022 Nov 26;55(1):35.
doi: 10.1186/s40659-022-00405-2.

Extracellular signals regulate the biogenesis of extracellular vesicles

Yong Jin  1 , Lele Ma  1 , Wanying Zhang  1 , Wen Yang  1   2 , Qiyu Feng  3 , Hongyang Wang  4   5
Affiliations
Review

Extracellular signals regulate the biogenesis of extracellular vesicles

Yong Jin et al. Biol Res. .

Abstract

Extracellular vesicles (EVs) are naturally released membrane vesicles that act as carriers of proteins and RNAs for intercellular communication. With various biomolecules and specific ligands, EV has represented a novel form of information transfer, which possesses extremely outstanding efficiency and specificity compared to the classical signal transduction. In addition, EV has extended the concept of signal transduction to intercellular aspect by working as the collection of extracellular information. Therefore, the functions of EVs have been extensively characterized and EVs exhibit an exciting prospect for clinical applications. However, the biogenesis of EVs and, in particular, the regulation of this process by extracellular signals, which are essential to conduct further studies and support optimal utility, remain unclear. Here, we review the current understanding of the biogenesis of EVs, focus on the regulation of this process by extracellular signals and discuss their therapeutic value.

Keywords: Exosome; Extracellular signal; Extracellular vesicle; Information transfer; Microvesicle; Signal transduction.

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Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
The biogenesis of the extracellular vesicle and its structure. a EVs can be divided into three subtypes: exosomes, microvesicles and apoptotic bodies. Exosomes are formed as ILVs in the MVBs. This process requires the involvement of ESCRT components, and it also occurs in ESCRT-independent pathways, including syntenin-, lipids- and tetraspanin-dependent mechanisms and others. After ILVs formation, MVBs are transported to the plasma membrane or the lysosome, which primarily involves some Rab proteins. Finally, MVBs fuse with the plasma membrane with the involvement of SNARE complex, and exosomes are released. Microvesicles are released directly after the outward budding from the plasma membrane, which primarily involves the ESCRT, ARRDC1, lipids, Rho proteins and Ca2+. Apoptotic bodies only generate from apoptotic cells and shed from the cell surface. Enveloped viruses that highjack the membranes for release can also be considered as a kind of EV. b The extracellular vesicle is made up of lipid bilayers and enriched in proteins, nucleic acids and lipids
Fig. 2
Fig. 2
Extracellular signals regulate the biogenesis of exosomes. Extracellular signals regulate different events during the biogenesis of exosomes in different cell types. Activated GPCR regulates neutral sphingomyelinase activity and ceramide to effect exosome release, induces the formation of ILVs via DAG/PKD, triggers exosome release via PLC/IP3/Ca2+ and participates in MVBs fusion with the plasma membrane via DAG/PKC. Activated EGFR activate ERK and HRS to promote cargo loading and exosome release. Inhibitory AKT/mTORC1 signals delivered by EGFR stimulate release from Rab11a compartments of exosomes. TNF-α triggers the release of exosomes which depends on sphingomyelinase. Cell death inducer stimulate TNFR, then TNFR promotes endosomal trafficking via RIPK3/MLKL pathway and enhances exosomes release. Wnt-mediated GSK3 inactivation regulates the expression of Rab27, and Wnt/β-catenin/TCF-4 activates the expression of Rab27B, therefore participating in the regulation of exosomes biogenesis. Hypoxia regulates exosome release through HIF-1α, Rab27A, Rab7, LAMP-1/2, neuraminidase-1 and ATM. Circadian clock and mechanical force also regulate exosome release, but specific mechanisms are unclear
Fig. 3
Fig. 3
Extracellular signals regulate the biogenesis of microvesicles. Microvesicles release directly from the plasma membrane and Rho signaling is one of the most important pathways mediating GPCRs signals regulation of microvesicle release. EGF activates EGFR to activate Cdc42, activated Cdc42 binds to IQGAP1 to block endocytosis and facilitate microvesicle release. Toxic lipid through TNFR activates DR5 proapoptotic signaling and ROCK1 to regulate plasma membrane-derived EV release. Wnt signaling regulates the expression of the Rab, Rho, ARF and Ca2+ to affect microvesicle release. Hypoxia regulates Rab22A expression through HIF-1α to affect microvesicle release. Shear force induces microvesicle release through integrin signaling and Scr/Rac1 signaling
Fig. 4
Fig. 4
The diagram of EVs in clinical application. a EVs participate in various disease progression including cancer, infectious diseases and neurodegenerative disorders. For example, tumor-derived EVs can help pre-metastatic niche formation, act within tumor environment by educating different types of stroma cells and propagate tumor heterogeneity. EVs become potential novel targets for therapeutic intervention. b The low immunogenicity, efficiency and stability of EVs make them promising vehicles for drug delivery. Exogenous and endogenous loading approaches can be applied. For example, EVs can be loaded with specific cargo through direct transfection, and cells can be engineered to express the therapeutic of interest. In addition, EVs can also be modified to help deliver to the desired site of action. c EVs contribute significantly to drug resistance. Exosomes encapsulate and export drugs, horizontally transfer drug efflux pumps to recipient cells, and transfer biomolecules that promote drug inactivation. d EVs reflect heterogeneous biological changes related to diseases, supporting disease prediction, diagnosis, prognosis and surveillance with simplicity and stability. Created with BioRender.com
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