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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 242

devoid of nuclei and membrane-bound organelles but enriched in selected membrane proteins and lipids
exposed at their membrane surfaces, and cytosolic components including both enzymatic and genetic
material. EVs, once released from healthy and diseased cells, can reprogram recipient cells for “good or
[8]
bad” . EVs have been reported to be involved in virtually every aspect of human health and disease, and
over the past years, diverse biological functions have been attributed to EVs depending on the cell types
from which they were released. Among the first studies was the observation that EVs promote sperm cell
motility by prostasomes (prostate cell-derived EVs) . This early report did not assign an origin or a
[9]
particular cargo associated with bioactive EVs. Studies by the teams of Rose Johnstone and Philip Stahl
reported that reticulocytes release transferrin receptor-rich vesicles during the differentiation process [10-13] .
[11]
The Harding et al. and the Pan and Johnstone papers demonstrated that the secreted vesicles were of
endosomal origin and released upon fusion of multivesicular endosomes (MVEs) with the plasma
membrane . These studies opened the possibility of a new intracellular trafficking pathway that caught the
[13]
interest of the cell biology community.

In metazoans, EVs impact communication and exchange among cells within tissues, within the circulation,
and even at the interface with the external environment such as in the microbiome [7,14] . A variety of reports
now confirm that EVs are players in the information exchange that occurs between cells at the tissue level,
in the nervous system (e.g., via exchange among and between astrocytes, glia and neurons) , in the
[15]
immune system (as initially revealed by the early pioneering work on exosomes and antigen
presentation [16,17] ) between B cell, T cells and dendritic cells, and in the integumentary system between
keratinocytes, melanocytes and fibroblasts among others [18,19] . Recent studies suggest that EVs may play an
important, if unforeseen, role in homeostasis in the endocrine system. EVs may deliver informational
content between tissues and cells that influence their subsequent responsivity to insulin [20,21] . Exercise studies
in particular have drawn much attention where EVs released in response to exercise appear to have a broad
[23]
influence on metabolism . Muscle releases exerkines that may be packaged in EVs . Similar to paracrine
[22]
signaling, but at longer distances, EVs may operate in parallel with the endocrine system, where EVs carry
integrative messages connecting tissues with tissues (e.g., adipose EVs and the brain) [Figure 1] . The
[21]
endocrine system evolved in metazoans, in part, as a spin-off from the nervous system, whereas EV
signaling probably evolved much earlier. Endocrine signaling and EV signaling, therefore, evolved in
parallel. EVs may play a role as an “invisible hand” that links the endocrine system to what is happening at
the tissue level.

Early reports revealed that cells release EVs, exosomes, in particular, for disposal of “unwanted” cellular
components as part of cellular housekeeping or as content that can be used for trophic support . EVs
[24]
[25]
can operate as “independent metabolic units” where they can influence the milieu of the microenvironment
or be exploited as signaling units between cells . At the tissue and organism levels, EVs can induce cellular
[26]
responses as initially reported in the immune system and in the central nervous system or in the
[17]
[27]
[16]
skin , among others. In the immune system, the ability of B lymphocytes to stimulate T cell proliferation
[18]
and the findings that EVs secreted by dendritic cells injected into mice bearing tumors can suppress not
[17]
only tumor growth but also tumor eradication has been exploited to enhance anti-tumor immune
responses in patients and influenced immunotherapy protocols [28,29] .
A growing interest has focused on regenerative properties associated with EVs released from mesenchymal
stem cells . Various reports have shown promising results in wound healing and in recovery from
[30]
ischemia and tissue fibrosis, among others [31,32] . Other interesting findings are the functions of placental-
derived EVs during pregnancy, from placenta establishment to maternal immune tolerance towards the
[33]
fetus and protection against viral infections . In pathological scenarios, on the “bad side of the coin” as it