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Page 243 Raposo et al. Extracell Vesicles Circ Nucleic Acids 2023;4:240-54 https://dx.doi.org/10.20517/evcna.2023.18

Figure 1. EV-based signaling. Information may be carried by individual EVs or via clusters of EVs. Clustered EVs may open the
possibility of a quorum mechanism of signaling often found in bacterial communication. EV-based information exchange appears to
[94]
influence all of the major organs and inter-organ homeostatic systems in metazoans, including the immune system , the nervous
[95] [8] [96]
system , the skin , and the endocrine system . Overall metabolism may be influenced by EVs released from muscle upon
[97]
exercise . In the endocrine system, the interplay between the macrophage and the adipocyte via EVs in the regulation of insulin
[96]
responsivity represents one example of a close collaboration between endocrine function and EVs . In these various examples, is the
conversation or information transfer between cells or tissues (as depicted above) a one-way signaling mechanism or is the information
transfer two-way? If information transfer were a two-way mechanism, what would be the nature of the return pathway-vesicular or
humoral? What are the complex feedback control mechanisms in play in participating cells? It remains to be seen.
were, EVs can induce tolerance in the immune system and promote tumor progression by being involved in
[34]
[35]
organotropism and metastasis or sustain infectious or inflammatory states . EVs may be involved in
pathogen transmission in neurodegenerative disease by ferrying prions and other protein cargo involved in
these diseases . Another example is that in viral infections such as SARS Cov2, EVs have been shown to
[36]
express the spike protein on their surfaces, thereby blocking the effectiveness of endogenous neutralizing
[37]
antibodies . Despite all the aforementioned downsides, whether delineating EV function in normal tissue
or in diseased states, expanding our knowledge pool carries an enormous payoff as it opens avenues for
varied diagnostic and therapeutic applications . Several bench-to-the-bedside applications of EVs are now
[38]
envisioned and exploited by established and emerging startups (https://bioinformant.com/top-exosome-
companies/)

REGULATED EV ASSEMBLY AND RELEASE APPEARS TO BE A UNIVERSAL
CHARACTERISTIC AMONG EUCARYOTIC CELLS
The goal of EV research is to achieve a comprehensive understanding of the depth and breadth of “EV
Biology” in all forms of life. Several large hurdles remain to capture this goal. These include vesicle
heterogeneity and its origins, isolation, using novel biophysical and biochemical methods and
compositional characterization (e.g., is there a single EV species with all the features necessary to mediate
cell-to-cell signaling) [7,39] . In connection with the latter is signaling or messaging due to a quorum effect as
found in bacteria. Lastly, assigning functions to specific EVs or groups of EVs is a universal goal among EV
research enthusiasts while developing an understanding of their biogenesis and targeting. EV nomenclature
has been and is a continuing challenge. The commonly used EV nomenclature encompasses both endo-
[39]
lysosome derived- and plasma membrane derived-vesicles . Complexity is further increased by the
findings that EVs released from cells are neither dispatched indiscriminately from endosomes nor random
sites in the plasma membrane, but rather from specific membrane domains including cell protrusions and
[43]
primary cilia [40,41] . Additional types of subcellular-derived structures are migrasomes , apoptotic bodies ,
[42]