Page 79 - Mesenchymal Stem Cell-Derived Exosomes as an Emerging Paradigm for Regenerative Therapy and Nano-Medicine

Therapeutic Potential of Mesenchymal Stem Cell-Derived Exosomes in the.. .

immune response by delivering immunosuppres- During the early stage of corneal damage, injured
sive factors to the effector immune cells (Lai et al. epithelial cells secrete the inflammatory cytokine
2010; Li et al. 2013; van Koppen et al. 2012; IL-1, which is stored in epithelial cells and
Zhang et al. 2014; Kordelas et al. 2014). released when the cell membrane is damaged by
It was recently revealed that exosomes derived external insults (Yamada et al. 2003). IL-1Ra has
from amniotic fluid derived MSCs (AF-MSCs) an important anti-inflammatory role in corneal
contain immunosuppressive factors TGF-β and protection and regeneration. When IL-1Ra binds
HGF. TGF-β suppresses activation of Jak-Stat to the IL-1 receptor (IL-1R), interaction between
signaling pathway in T cells, causing the G1 cell inflammatory IL-1 and IL-1R is prevented.
cycle arrest (Volarevic et al. 2017; Bright et al. Accordingly, various pro-inflammatory events,
1997) while HGF acts synergistically with TGF-β initiated by IL-1:IL-1R interaction, including the
enabling suppression of T cell proliferation and synthesis and release of chemokines, and
attenuation of T cell-mediated inflammation enhanced influx of neutrophils, macrophages,
(Volarevic et al. 2017; Di Nicola et al. 2002). In and lymphocytes in injured corneas are inhibited
line with these findings, when (Balbi et al. 2017). In line with these
phytohemagglutinin-stimulated peripheral blood observations, our preliminary findings suggest
mononuclear cells [PB-MNCs] were cultured in that IL-1Ra containing AF-MSC-derived oph-
the presence of TGF-β and HGF-containing AF- thalmic solution significantly attenuated inflam-
MSCs-derived exosomes, proliferation of mation in patients suffering from corneal injury.
PB-MNCs was notably reduced and their apopto- Similarly, as for progression of corneal injury,
sis was significantly enhanced (Balbi et al. 2017). inflammation has crucial role in the pathogenesis
Similarly, maturation and proliferation of B cells of DED, multifactorial disease of the tears and
was reduced and their capacity for production of ocular surface that results in symptoms of dis-
antibodies was suppressed, indicating strong comfort, visual disturbance, and tear film instabil-
immunosuppressive potential of AF-MSCs- ity (Gayton 2009). It is well known that Th17
derived exosomes (Balbi et al. 2017). Interest- cell-driven inflammation plays important role in
ingly, among PB-MNCs, AF-MSC-derived the pathogenesis of DED (Théry et al. 2009).
exosomes did not attenuate proliferation of Inflammatory dendritic cells (DCs), in IL-1,
immunosuppressive CD4 + CD25 + FoxP3+ T IL-6, and IL-23 dependent manner induce differ-
regulatory cells, confirming significance of AF- entiation of naïve T cells into Th17 cells which
MSC-derived exosomes as potentially new thera- reduce tear production and promote progression
peutic agents in the therapy of inflammatory of DED in IL-17 dependent manner (Gayton
diseases. 2009; De Paiva et al. 2009). AF-MSCs, through
In line with these findings, we recently devel- the production of immunomodulatory GRO,
oped immunomodulatory ophthalmic solution attenuate maturation and antigen-presenting func-
(“Derived Multiple Allogeneic Proteins Paracrine tion of inflammatory DCs and suppress Th17
Signaling “D-MAPPS”) the activity of which is immune response. At the same time, AF-MSC-
based on the activity of AF-MSC-derived derived GRO promote generation of regulatory
exosomes, cytokines and growth factors capable DCs capable to produce high levels of anti-
to attenuate inflammation in the eye: IL-1 recep- inflammatory IL-10 (Merino-González et al.
tor antagonist [IL-1Ra], indoleamine 2016; Nakamura et al. 2015; Yi and Song 2012)
2,3-dioxygenase (IDO) and growth related onco- creating immunosuppressive microenvironment.
gene (GRO). Based on our preliminary results, Similarly, MSC-derived IDO acts as a critical
this product had beneficent effects in treatment of molecular switch that simultaneously blocks
corneal injuries and dry eye syndrome (DED). re-programming of Tregs into inflammatory,
Corneal injuries are usually complicated with IL-17 producing effector Th17 cells having
the influx of immune cells and consequently important role in Treg-based immunosuppression
developed inflammation (Dana et al. 2000). of Th17 driven inflammation (Volarevic et al.