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Raposo et al. Extracell Vesicles Circ Nucleic Acids 2023;4:240-54 https://dx.doi.org/10.20517/evcna.2023.18 Page 248

understanding of the role of EV information transfer during close encounters, in this case in the
immunological synapse, but potentially in other physiologically important cell interactions such as the
[81]
retina .

EVs can also directly interact with and remodel the cell environment. As an example, melanoma-derived
EVs can interact physically with collagen. EVs modulate the extracellular matrix which could have
consequences on their diffusion in the tumor microenvironment and therefore affect the capacity of EVs to
interact with the different cell types that constitute the tumor microenvironment .
[82]

SYSTEMS TO SIMULATE EV SIGNALING “IN VITRO” AND “IN VIVO” - DELINEATING
THEIR ROLE IN TISSUE PHYSIOLOGY AND PATHOPHYSIOLOGY
One of the goals of EV research is to understand their role in tissue homeostasis. To achieve this goal,
investigators have developed “in vitro” approaches simulating organ environments, including the heart,
adipose tissue, and skin, among others. More recently, iPSC-derived organoids have been developed to
simulate various tissue environments, including the brain which have been particularly illuminating . Skin,
[83]
the largest organ in the organism, has appeared as a fascinating puzzle to understand EV biology and their
functions in homeostasis and disease . In the skin epidermis, melanocytes embrace around forty
[84]
keratinocytes with their extended dendrites [Figure 3]. They are in close contact with each other
establishing a so-called “pigmentary synapse” in which caveolae play an essential role in mechano-signaling
and pigment transfer . Keratinocytes and melanocytes secrete factors that are required to control skin cell
[85]
function . In addition to soluble factors, they also secrete EVs carrying proteins, lipids and genetic material
[86]
that can be involved in controlling cell-cell contacts and several aspects of skin homeostasis [Figure 3].
Keratinocytes secrete EVs with features of exosomes, enclosing specific miRNAs that are targeted to the
melanocytes to control the expression of melanosomal proteins and, consequently, modulate
pigmentation . In a feedback loop, melanocytes secrete a heterogeneous population of EVs that are likely
[18]
to regulate keratinocyte biology and functions (our unpublished studies). Any deregulation in these
pathways may underlay pigment disorders . Moreover, they may be involved in pigmentary disorders in
[87]
which intercellular communication is altered and in skin melanoma and carcinoma where they potentially
contribute to the progression of metastasis [88,89] . Other cells present in the skin, such as dermal fibroblasts,
can also secrete EVs or be the recipient of keratinocyte and melanocyte EVs, establishing a communication
network within a complex tissue . Clearly, these are important components of the overall homeostasis of
[90]
the skin. EVs and their signaling capacities could be used in therapeutic strategies in skin regenerative
medicine by exploiting stem cells .
[91]

CONCLUSIONS
Membrane trafficking came of age, starting with the description of the secretory pathway and the lysosome
in the middle part of the last century, as set out in the Introduction. The various Nobel prizes awarded along
the way serve as markers for the amazing progress achieved during this period and up to time present. With
the discovery that cells can selectively package and secrete content in vesicular form and that the secreted
vesicles can act in cell signaling, a new chapter in membrane trafficking has emerged. Vesicle secretion by
bacteria and eucaryotic cells has been known for years, but the idea that signaling information can be
[92]
transferred between and among cells has introduced a new lens in viewing physiology in animals and
plants . Consequently, the entire cell biology community, along with researchers in physiology and
[93]
pathophysiology, have been sparked by curiosity - how are information-containing vesicles formed and how
is information packaged; moreover, what are the downstream targets of such vesicles and what is the new
molecular language of recognition that allows delivery of information to target cells. The puzzle has many
components-at this point, we know that information containing vesicles can be generated at the plasma