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Page 28 Chakraborty et al. Extracell Vesicles Circ Nucleic Acids 2023;4:27-43 https://dx.doi.org/10.20517/evcna.2023.05

Keywords: Tunneling nanotubes, intercellular communication, neurodegenerative diseases

INTRODUCTION
Mechanisms of intercellular communication: extracellular vesicle vs. membrane protrusions
In animals, intercellular communication can occur at different scales. Some mechanisms rely on the release
of secretory molecules in the extracellular environment upon the fusion of intracellular vesicles with the
plasma membrane. In the peculiar case of hormones, these molecules can travel through the circulatory
system and reach membrane receptors of distant cells. However, the signal spreading often takes place
within a few hundred microns only, as it relies on the local concentrations of the signaling molecules, which
decrease in an exponential fashion as diffusion in tissues occurs . Other mechanisms involve the transport
[1]
of extracellular vesicles (EVs). Encapsulated ions, proteins, RNAs, or even the lipid and protein content of
the vesicles itself can trigger intracellular responses and phenotypic changes following their uptake by
neighbor cells. Such responses usually include regulation of pro-/anti-inflammatory pathways, as described
[2,3]
in excellent reviews . Consequently, this mode of communication involves material transfer between cells
and can therefore be used by pathogens as a route for spreading, as has been demonstrated for the Hepatitis
Sc [4-6]
C Virus (HCV), or for the aggregate-prone prion protein Scrapie (PrP ) and for different protein
aggregates accumulating in neurodegenerative diseases (NDs), as will be discussed subsequently.
Additionally, EVs represent important regulators of the immune response by transporting antigens to
immune cells . Through different formation mechanisms, the composition of these vesicles is finely tuned
[7]
to have them interact with surrounding cells in a specific or non-specific manner to induce a wide range of
[11]
responses [8-10] . Despite the development of new promising tools enabling single-vesicle analysis , we are
only beginning to understand the diversity of EVs. In fact, the current limitations of the methods used to
purify a single population led the International Society for Extracellular vesicles to recommend the use of
the terminologies “small EVs” (< 200 nm) and “large EVs” (diameter > 200 nm) . Furthermore, different
[12]
formation mechanisms for EVs have been identified. Exosomes (diameter < 50-150 nm), for example, form
within the lumen of early endosomes (EE), the latter eventually maturing into multivesicular bodies
(MVBs). Upon fusion of MVBs with the plasma membrane, exosomes are released in the extracellular
environment. On the other hand, ectosomes (also called microvesicles with a diameter of 100-500 nm) form
via direct budding from the plasma membrane [Figure 1A]. Importantly, for both exosomes and ectosomes,
luminal and membrane composition greatly varies within a single cell and across different cell types,
possibly conferring different functions on them . Another subtype of EVs, called migrasomes, has been
[13]
described to have putative roles in intercellular communication. Migrating cells leave behind a trail of these
organelles containing Tetraspanin-enriched microdomains , which can then be taken up by other cells,
[14]
thereby transferring their contents, a phenomenon referred to as migracytosis .
[15]
In addition to secretory vesicles, other intercellular communication mechanisms effective at smaller ranges
rely on direct cell-to-cell contact. Filopodia, for example, are very dynamic short cellular protrusions
(usually less than 5 µm in length) that allow intercellular signaling without material exchange. Such
signaling is mediated by surface receptors present on the filopodial tip, such as Cadherins or Integrins .
[16]
[17]
The binding of such receptors directly at the tip or indirectly (through the transduction of mechanical
force(s) via the Actin bundle to the base of the filopodial shaft) triggers Ras superfamily-mediated
downstream signaling, subsequently leading to various cellular responses [17,18] . Thus, by regulating
expression, subcellular localization and activation of these receptors or ligands, cells have a way to sense and
communicate with their microenvironment. Filopodia also favor cell migration, playing major roles in
cancer and wound healing [19,20] . Some specialized filopodia-like protrusions are cytonemes, which can reach
up to 700 µm long, allowing the transfer of signaling molecules between cells at contact sites called