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Page 45 Racchetti et al. Extracell Vesicles Circ Nucleic Acids 2023;4:44-58 https://dx.doi.org/10.20517/evcna.2023.03

communication and contributes to their clinical applications.

Keywords: Autophagosomes, cargo, ectosomes and exosomes, endocytosis, endo-lysosomes, exocytosis,
extracellular vesicles (EVs), lysosome storage disorders (LSDs), membrane fusions, microdomains, multivesicular
bodies (MVBs), unconventional protein secretion (UPS)

INTRODUCTION
To begin the first review in this Special Issue dealing with intercellular communications, we highlight four
intracellular, membrane-bound structures involved in the direct generation of distinct vesicles ultimately
released into the extracellular medium. These structures differ, and their vesicles are characterized by
distinct properties depending on their nature: origin, generation, intracellular processes and pathways, and
discharge. Given these differences, the vesicles from each structure are indicated by a distinct name. In
contrast, upon their release, all such vesicles are denoted with the same name, extracellular vesicles (EVs).

[1-5]
Initially, we will cover the discovery of the first two types of membrane-bound structures . The first,
observed initially by electron microscopy, was called by a name still employed, MultiVesicular Body
[5]
(MVB) . The identification of MVBs as endocytic vacuoles, in particular for their luminal generation and
accumulation of small vesicles (50-150 nm), occurred about 35 years ago. Initially called intraluminal
vesicles, these vesicles become exosomes upon their release into the extracellular space. Since, however, the
exosome name has been employed in the scientific community we will employ it in the context of all
cellular conditions, from their generation to their release to the extracellular medium, where all released
vesicles are called EVs.

The second membrane-bound structure, identified about 35 years ago, comprises several plasma membrane
microdomains. The larger vesicles (150-400 nm), grown outwardly, are then released extracellularly from
the cell surface. Given their direct extracellular release, the vesicles of our second type are considered
independent from the others. For decades, therefore, they were given names unreasonable for larger
vesicles: microvesicles, microparticles, shedding microvesicles, and others . Currently, such names have
[6]
been replaced mainly by ectosomes, a name analogous to (but distinct from) exosomes, i.e., the two vesicles
end up outside the cells; however, their properties (and thus their names) are different.

The other two cytoplasmic membrane-bound structures involved in communication are specialized forms
of two cytoplasmic organelles, lysosomes, and large autophagosomes. Upon their discovery over 60 and 50
years ago, respectively, these organelles were believed to carry out only a few functions, some dependent on
their fusion: uptake, digestion, and elimination of cytoplasmic molecules and structures. Additional
functions of these organelles, due to their exocytoses followed by extracellular discharge of cargo
components, were discovered approximately 20 and 10 years ago, respectively [7-10] .

Regarding dynamic properties, including release and navigation through the extracellular medium, two
essential processes occur in the four specific intracellular membrane-bound structures. First, they often
respond to stimulation, for example, activation of receptors or stressful conditions; second, they mediate
other fusions (usually called “prefusions”) with vesicles or cisternae of the endocytic system, which are the
structures taken up by all cells to equilibrate surface enlargements dependent on exocytoses and other
processes [11,12] . Prefusion with endocytic components is essential for intracellular cytoplasmic structures to
perform additional fusions with other cytoplasmic membranes. Studies in the last decade have
demonstrated that the various types of membranes need to have experienced prefusions with endosome