Page 40 - 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 3 of 10

ionophores [40]. Aside from immune cell-derived exo- from B cells to SGECs. This functional miRNA targeted
somes, exosomes secreted by nonimmune cells such as aquaporin 5 (AQP5) and stromal interacting molecule 1
tumor and mesenchymal stem cells (MSCs) have gained (STIM1), which could significantly impact salivary secre-
great attention in recent years. Tumor-cell-derived exo- tion. However, the authors did not mention the effect on
somes can travel to the draining lymph node, where they the function of LGs [52].
inhibit T cell activation by presenting programmed The LGs are primarily responsible for the aqueous
death-ligand 1 (PD-L1) and thus promote tumor pro- layer of the tear film. LG dysfunction is mainly due to
gression [41]. Mesenchymal stem cells-derived exosomes the infiltration of immune cells [75]. Our research team
(MSC-Exos) have been shown to enhance the differenti- has verified that MSC administration efficiently allevi-
ation of immunosuppressive cells such as M2 macro- ated induced autoimmune dacryoadenitis in rabbit
phages and Tregs, or inhibit proliferation of natural models, which closely mimic human SS [76]. It is noted
killer cells or T lymphocytes [42]. For instance, Zhao et that MSC-Exos mediate the immunosuppressive effects
al. discovered that mouse bone marrow-derived MSC- of their parent cells and are deemed as promising surro-
Exos modulated macrophage polarization by transferring gates for MSC-based therapy [33]. Ongoing studies in
miR-182, which targeted TLR4/NF-κB/PI3K/Akt signal- our laboratory recently demonstrated that subconjunc-
ing [43]. More attractively, several studies proposed that tivally administered MSC-Exos efficiently improved clin-
inflammatory stimulation increased secretion of MSC- ical evaluations and diminished the inflammation in
Exos and even enhanced their anti-inflammatory and lacrimal glands of diseased rabbits, compared with those
immunosuppressive properties [44–46]. However, al- treated with saline. The therapeutic effects may partially
though exosomes possess versatile biological functions be ascribed to their modulatory effects on lacrimal
including immunomodulation [47], pro-regeneration macrophage polarization and enhancement of Treg and
[48], anti-inflammation [49], and tumor growth regula- Th2 responses via targeting NF-kB signaling. Therefore,
tion [50] (Table 1), the field of exosome research in eye MSC-Exos presumably provide a very promising cell-free
diseases currently remains relatively less explored. therapy for SS dry eye. In addition, the role of exosomes
in interactions between lymphocytes and LG epithelial
Exosomes in immune-mediated eye diseases cells remains unexplored, calling for extensive research.
Sjögren’s syndrome (SS) dry eye
Sjögren’s syndrome (SS), a multisystem autoimmune dis- Corneal allograft rejection
ease, is characterized by lymphocytic infiltration in salivary Corneal transplantation is the most prevalently performed
and lacrimal glands (LGs) and the presence of various auto- type of tissue grafting globally. To enhance corneal graft
antibodies (such as anti-Ro(SS-A) or anti-La(SS-B)), result- survival, considerable efforts have been devoted to build-
ing in oral and ocular dryness [67, 68]. This condition leads ing effective strategies [77]. Although cornea as an avascu-
to one of the most severe subtypes of dry eye diseases [20]. lar transparent tissue enjoys the relative privilege of
Activation of both innate and adaptive immune pathways, immunity, the major cause of corneal graft failure re-
such as interferon (IFN) signatures, B cell activating factor ported is allogeneic rejection, which is ascribed to the
(BAFF)/BAFF receptor axis, and NF-kB signaling, contrib- adaptive immune response initiated through recognition
utes to the pathogenesis of SS [69, 70]. of donor MHC antigens by recipient T cells after trans-
Salivary gland epithelial cells (SGECs) in SS play active plantation [78, 79]. EVs, including exosomes, released by
roles in the autoimmune and inflammatory responses by donor cells are partly responsible for this type of allore-
virtue of the constitutive or inducible expression of diverse cognition [80]. Howbeit, they also contribute to allograft
immunoactive factors, such as BAFF, several Toll-like tolerance under certain circumstances. It has been re-
+
receptors (TLRs), and autoantigenic ribonucleoproteins ported that EVs from a specific population of CD4 CD25 −
(RNPs) [71, 72]. Lymphocytic infiltrates consisting primar- Tregs generated in vitro could prolong kidney allograft
+
ily of CD4 T cells and B cells occur proximally to and survival, which was mediated by their unique cargo, spe-
frequently invade epithelial cells [73, 74], suggesting the cific miRNAs, and inducible nitric oxide synthase (iNOS)
interaction between epithelial and immune cells. One pre- enzyme [53]. Moreover, MSC-Exos loaded with specific
vious study demonstrated that the autoantigenic Ro/SS-A, small RNAs successfully improved islet transplantation
La/SS-B, and Sm RNPs were present in exosomes which [54]. These encouraging results suggest that exosomes
were released continuously by SGECs, indicating that from specific immunosuppressive cell populations serve as
intracellular autoantigens were transferred to autoreactive a potentially effective tool to promote immune tolerance
lymphocytes via RNP-containing exosomes. However, this in graft survivals such as corneal graft.
release is not restricted to SS-derived cells [51]. Besides, as For decades, severe global shortfall of donated human
EBV typically infects B cells, one study proposed that corneas has been an ongoing challenge that should not be
EBV-miRBART13-3p could be transferred via exosomes ignored [81]. To address this, new biomaterials, such as