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Page 4 of 13 Berezin et al. Vessel Plus 2020;4:15 I http://dx.doi.org/10.20517/2574-1209.2020.03

structure of microvesicles is extremely variable and includes membrane regulatory (Rab, Sterol Carrier
Protein 2) and structure (β-actin, α-actin-4) proteins, heat shock proteins HSP90AB1, adhesive molecules
(ICAMs, PECAM-1, MCAM), lipids (SpL, PL, LPS, LPS) and receptors (tetraspanin’s receptors, LAIR-1,
EGFR), enzymes (superoxide dismutase, Rab GTPase, cytochrome complex, Akt/ERK, triosephosphate
isomerase -1, 3-Hydroxy-3-Methylglutaryl-CoA Lyase), immune system proteins (CD14, CD276, MiC-11),
and apo-lipoproteins (apo-A-II) [24-26] . Therefore, microvesicles may yield several non-coding RNAs and
[27]
chromatin fragments coupled with the complexity of other components .
Apoptotic cell-derived EVs
Apoptotic cell-derived EVs include two types of apoptotic bodies: large membrane-bound vesicles [large
apoptotic bodies (ABs) with diameter ≥ 1000 nm] and small apoptotic microvesicles (small ABs with
[28]
diameter < 1000 nm) . ABs are particles that are generally larger in size in comparison to both exosomes
[29]
and microvesicles but have a variable diameter that fluctuates around 1000 nm (from 1000 nm to 2000 nm) .
Both types of ABs result from blebbing of the surface of apoptotic cells and contain proteins, numerous cell
[30]
organelles and chromatin fractions, such as non-coding RNAs from the nucleus or nucleoli . The process
of AB generation is controlled by several distinct morphological steps (i.e., membrane permeability and
blebs, membrane protrusion, and cell fragmentation), which are, in turn, regulated by several molecular
factors including the Rho-associated protein kinase and the plasma membrane channel pannexin-1.

ABs contain mitochondria, MHC II molecules, ICAM-3, phosphatidylserine, sialylated and glycosylated
ligands, fragments of chromatin, DNAs, and non-coding RNAs. It has been noted that the packaging of
chromatin content (DNAs and non-coding RNAs) into the structure of ABs is regulated by apoptosis
[31]
and there are indeed, ABs with no fragments of chromatin or very low amounts of DNAs . ABs are also
classified depending on their origin from the mother cells including antigen-presenting cells, mononuclear
[32]
cells, endothelial cells, fibroblasts, cardiac myocytes, and epithelial cells . The clearance of ABs has been
[33]
ensured by phagocytes . To accurately differentiate ABs from other particles including cells and debris,
[34]
there are several specific surface markers such as Annexin A5/phosphatidylserine .
Biological role of EVs
The key biological functions of EVs that originate from various cells are cell-to-cell communication
and the transfer of materials called the secretome. Acting as cargo for numerous molecules [heat shock
proteins (HSP-90, HSP-70), ILs, tumor necrosis factor-alpha, active molecules, enzymes, peptides, growth
factors], EVs are recognized by target cells through specific antigens, bind and fuse with them to supply
the packaged materials within to the cells. Therefore, small and medium/large EVs have wide range of
biological functions including immune response, antigen presentation, and the transfer of RNA and
DNA [29,35] . The full spectrum of pleiotropic effects of circulating EVs is shown in Figure 1.

Recent studies have revealed that EVs may contain inactive forms of non-coding RNAs, which can be
transferred to another cell and become functional in that new microenvironment [36,37] . Indeed, there
is strong evidence that hypoxia and ischemia are triggers for monocyte-dependent production of pro-
inflammatory cytokines including IL-2 and TNF-alpha, and the supply of these cytokines to target cells
[38]
are mediated through package as cargo into EVs . On the other hand, HSPs, growth factors, non-coding
RNAs, and active molecules, which are all transferred by EVs, are involved in the regulation of reparative
response, immune reactions and cytoprotection [39,40] . The wide spectrum of biologically active molecules
that are transported by EVs from the mother cells to target cells are able to regulate the endogenous repair
system activity including proliferation, differentiation and migration of endothelial progenitor cells and
angiogenesis [41,42] . Through appropriate receptor-ligand (integrin αvβ3, CD40 ligand, neuregulin-1, VE-
cadherin and beta-catenin) interactions and the cargo content of EVs, the intracellular signaling pathways