Page 39 - Mesenchymal Stem Cell-Derived Exosomes as an Emerging Paradigm for Regenerative Therapy and Nano-Medicine

Li et al. Stem Cell Research & Therapy (2019) 10:278 Page 2 of 10

produced in the lumen of the late endosomes (also [28–30], or via acting on their cell surface, without deliv-
called multivesicular bodies, or MVBs). MVBs eventually ery of their cargos [31] (Fig. 1). Nevertheless, the more
fuse with the plasma membrane and release their in- specific cellular and molecular basis for exosome target-
ternal contents as exosomes. Alternatively, some MVBs ing is still undetermined.
are destined for degradation inside of lysosomes [3, 14] The function of exosomes was unknown until 1996,
(Fig. 1). Cargoes assembled into exosomes are sorted when it was found that exosomes derived from Epstein-
through several molecular machinery, including the Barr virus (EBV)-transformed B cell lines induced major
endosomal sorting complex required for transport histocompatibility complex (MHC) class II-restricted T
(ESCRT) machinery (containing ESCRT-0, ESCRT-I, cell responses in an antigen-specific manner, hinting the
ESCRT-II, and ESCRT-III) and ESCRT-independent possible role of exosomes as mediators of immune re-
machinery (involving lipids, syndecan, and syntenin) [24, sponses [32]. Since then, intensive research has been de-
25]. In addition, the Rab family of small GTPase proteins voted to delineating their roles in immunomodulation. It
(such as Rab27a and Rab27b), SNARE (soluble N-ethyl- is now clearly understood that immunologically active
maleimide-sensitive fusion attachment protein receptor) exosomes can regulate both innate and adaptive immun-
complexes, and cytoskeleton act as important modula- ity [33, 34]. Exosomes generated by immune cells have
tors of exosomes secretion [24]. However, in spite of the been studied extensively. For instance, exosomes from
heightened interest in this field, the mechanisms that antigen-presenting cells including dendritic cells (DCs),
control exosome biogenesis and secretion are still not B cells, and macrophages carry surface MHCI and
+
exhaustive. MHCII molecules and thus directly stimulate CD8 and
Once released, exosomes can interact with specific re- CD4 + T cell responses, respectively [15, 35]. Besides,
cipient cells. It appears that exosome targeting specificity Okoye et al. demonstrated that Let-7d-containing exo-
is based on the particular combination of exosomes and somes derived from primary regulatory T cells (Tregs)
acceptor cells [24]. Studies have identified that the ex- inhibited Th1 cell responses by targeting Cox-2 in a
pression of phosphatidylserine receptors, integrins, tetra- mouse model of colitis [36]. Of note, exosome secretion
spanins, lectins, glycans, and other adhesion molecules in immune cells is regulated by cell context. For ex-
on exosome surface contributes to this process [26, 27]. ample, exosome release in DCs and B cells is increased
Exosomes can transmit information to target cells via after cognate T cell interactions [37–39], and mast cells
internalization through macropinocytosis, phagocytosis, produce more EVs in response to cross-linking of the
receptor-mediated endocytosis, or membrane fusion high-affinity Fc receptor for IgE or exposure to calcium

Fig. 1 Biogenesis, release, and internalization of exosomes. Exosomes originate from early endosomes which then mature to late endosomes or
MVBs. Numerous proteins, nucleic acid, and lipids are selectively encompassed in exosomes during the formation of ILV inside MVBs via the
invagination of the endosomal membrane. Eventually, exosomes are released outside the cell upon fusion of MVBs with the plasma membrane.
The internalization of exosomes by recipient cells can be mediated by receptor-mediated endocytosis, macropinocytosis, phagocytosis, or direct
fusion of exosomes with cell membrane