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Page 245 Raposo et al. Extracell Vesicles Circ Nucleic Acids 2023;4:240-54 https://dx.doi.org/10.20517/evcna.2023.18

Table 1. Examples of subpopulations of Extracellular Vesicles
Extracellular Vesicles Size Markers Biogenesis
Exosomes 30 nm-110 Tetraspanins (CD63) Correspond to the intraluminal vesicles of MVEs. They are
nm ESCRT complex subunits and generated by inward budding of the endosomal membrane
associated proteins (Tsg101, and they are secreted upon fusion of MVEs with the plasma
Alix) membrane
Syntenin
Ectosomes (microvesicles, 50 nm- Annexin A1, ARF6 Generated by outward budding from the plasma membane. In
oncosomes) 10,000 nm some cell systems, they can be formed at specific sites such
as membrane protrusions
Migrasomes 500 nm- TSPAN4 Generated during cell migration from long retraction fibers.
3,000 nm “pomegranate-like structures”, morphologically similar to
MVEs, are formed on these fibers and then released
Secretory Not LC3 Generated through macroautophagy (secretory
autophagosomes/Amphisomes determined autophagosomes) or fusion of autophagosomes and MVEs
Exomeres < 50 nm Enriched in proteins Involved Unknown but defined as “non-membranous”
in metabolic pathways
Apoptotic bodies 50 nm- Phosphatidylserine Released from apoptotic cells upon activation of apoptosis-
5,000 nm related transduction pathways
Released Midbodies 200 nm-600 Tubulin Released by dividing cells during cytokinesis and can induce
nm MKLP2 cell proliferation once uptaken by recipient cells
CEP55

mechanisms that operate at both sites [Figure 2]. Ceramide production has long been shown to be essential
[57]
for the sorting of proteolipids in oligodendrocytes . Tetraspanins, including CD63 that form
microdomains at the endosomal membrane, are required for the sorting of particular cargoes . Moreover,
[58]
syntenin and syndecans, together with Alix, an ESCRT accessory protein, are also important for ILV
formation and therefore for exosome secretion . Despite that some components of the sorting machinery
[59]
appear to act preferentially at the plasma membrane rather than on the endosomal system (ARF6,
CD133/prominin) [60,61] , the redundancy built into these various molecular machineries together creates a
roadblock to experimentally modulate their biogenesis, release and therefore their function. One should
consider the cargo of interest that recruits and pairs with particular machinery for sorting at the endosomes
or at the plasma membrane.

Because of the built-in redundancy, interfering with any single cog in the machinery is insufficient to
modulate EV secretion. While sorting machineries are thought to cluster and enrich cargoes on
microdomains that bud into EVs, cargoes, and their post-translational modifications, recruit the
appropriate sorting machineries. EVs, once released from cells, are targeted to their physiologically relevant
recipient cells to elicit cellular responses. EVs can also be internalized by reticuloendothelial cells such as
macrophages. How EVs find their targets and how their contents are specifically delivered and processed is
far from being elucidated. Depending on the cell type and cargo sequestered, the mechanisms may vary. The
diversity of mechanisms correlates with the heterogeneity in size and composition of ILVs that give rise to
different exosome subpopulations that may execute different functions .
[7]
Cargo plays a role. Expression of a single cargo protein targeted to MVEs can turn the recipient endosomes
into secretory endosomes. As an example, the expression of MHC class II in Hela cells allows the
recruitment of the small GTPase Rab27 to MVBs while increasing the release of MHC II-positive
exosomes . Interestingly, Rab27a is associated with most, if not all, secretory lysosomes (so-called
[62]
Lysosome Related Organelles), which indicates that secretory MVEs display features shared with organelles
of the LRO family such as melanosomes, cytolytic and basophilic granules, mast cell granules, platelet dense
granules . This suggests that secretory MVEs correspond to a subpopulation of bona fide MVEs whose
[63]
normal or main fate is to fuse with lysosomes leading to the degradation of endogenous or internalized