Page 27 - Mesenchymal Stem cells, Exosomes and vitamins in the fight aginst COVID

Al-Khawaga and Abdelalim Stem Cell Research & Therapy (2020) 11:437 Page 8 of 33

Anti-inflammatory and antiproliferative effects of MSCs MSCs can affect on the endothelial differentiation of
MSCs reduce the pro-inflammatory effect of DCs by sup- endothelial progenitor cells in vitro, mainly dependent
pressing their secretion of TNF [82]. Also, plasmacytoid on VEGF [94]. Human leukocyte antigen-G5 (HLA-G5)
DCs (pDCs), a set of specific cells for the secretion of high is another soluble factor secreted by MSCs and its secre-
levels of type I IFN, increase the production of IL-10 fol- tion is IL-10-dependent. HLA-G5 is required to suppress
lowing the incubation with MSCs [82]. MSCs can further the function of T lymphocytes and NK cells and to acti-
inhibit the cytotoxic activity of resting NK cells by redu- vate regulatory T cells [95]. Galectin-1 and 3 (Gal-1 and
cing the production of natural cytotoxicity receptor 3 Gal-3) as well as Semaphorin-3A (Sema-3A) are other
(NKp30) and natural-killer group 2, member D (NKG2D), secreted MSC immune regulators, known for their in-
involved in the activation of NK cells and target cell killing hibitory activities. Gal-1 and Sema-3A are two soluble
[83]. Therefore, MSCs inhibit NK cell proliferation and factors that can suppress T cell proliferation via
IFN production [84, 85]. Also, neutrophils are important neuropilin-1 (NP-1) binding [96, 97]. MSC-derived Gal-
cells of innate immunity, undergoing a process known as 1 significantly regulates the release of TNFα, IFNγ, IL-2,
the respiratory burst when binding to an antigen. MSCs and IL-10 [97].
have been reported to eliminate the respiratory burst and Finally, interleukin-1 receptor antagonist (IL-1Ra) and
to prevent the neutrophil cell death by an IL-6-dependent programmed death-1 (PDL1) are among the other se-
mechanism [86]. Also, MSCs play a key role in the adap- creted regulators of MSCs. IL-1Ra is among the anti-
tive immune system, where it inhibits the proliferation of inflammatory cytokine produced by MSCs, which can in-
T cells activated with antigens [76]. This leads to a reduc- hibit Th17 polarization. IL-1Ra expression tends to in-
tion in the IFN production and an increase in IL-4 pro- crease in MSCs exposed to IL-1β,TNF-α, and IFN-γ.
duction by T helper 2 (T2) cells, indicating a change in T Th17 cells induce the upregulation of PDL1, playing a
cells from a pro-inflammatory (IFN-producing) to an anti- major role in activating the MSC immunosuppressive ef-
inflammatory (IL-4-producing) state [82]. fect [98]. PDL1 further support the cell-cell contact
Furthermore, MSCs have been shown to downregulate through MSC-mediated inhibition on Th17 cells [98].
+
CD8 cytotoxic T lymphocytes (CTL)-mediated cytotox- MSC enhanced PDL1 ligand secretion suppress the activa-
+
icity [87] and further inhibit B cell expansion in vitro. tion of CD4 T cells and downregulate IL-2 secretion [99].
Also, MSCs can suppress B cell differentiation and the
constitutive secretion of chemokine receptors, affected MSC-derived exosomes
by the MSC-mediated suppression of T cell functions Extracellular vesicle (EV) is a term including both exo-
[88]. Furthermore, MSC-derived IDO has been shown to somes and microvesicles (MVs). The exosome diameter
be required in the inhibition of the expansion of IFN- is less than 200 nm, while MV diameter can reach up to
secreting Th1 cells and, together with PGE2, to stop NK 1000 nm. The secretomes of MSCs and their vesicles
cell activity [89]. offer a powerful tool for cell-free therapy due to their
paracrine and/or endocrine effects [100]. This strategy
Anti-apoptotic and protective functions of MSCs bypasses most of the safety concerns related to cell-
Several pro-inflammatory molecules modulate the im- based therapy, such as contamination with oncogenic
munosuppressive, trafficking, and paracrine potential of cells and continuous cell proliferation [101]. The key
MSCs. Enhanced paracrine potential of MSCs induced features of MSC-derived EVs are (1) non-proliferative,
by TNF-α, IL-1b, and nitric oxide (NO), ultimately which reduce the risk of tumor formation; (2) negative
increases MSC secretions of regenerative, immunomod- for HLA-I and HLA-II, which can be induced, and
ulatory, and trafficking molecules, including the key fac- therefore, they can be used from other individuals with-
tor, insulin-like growth factor 1 (IGF-1) [90]. Heme out any risk of immune response; (3) small in size allow-
oxygenase-1 (HO-1) is upregulated by TNF-α, IL-1α,or ing them to pass from the small blood capillaries; and
NO in endothelial cells or alveolar cells, where MSCs (4) stored without using DMSO, which may change their
overexpressing HO-1 showed an increase in the anti- characteristics [102]. EVs bind to a receptor on the cell
inflammatory, anti-apoptotic, and vascular remodeling membrane of the targeted cells, where they merge with
properties [91]. Upregulation of HO-1 increases produc- the membrane to secrete the EV contents inside the cell
tion of trophic molecules, such as FGF2, and IGF-1, and or enter into the cytoplasm in the form of endocytic ves-
VEGF [90]. Fibroblast growth factor-10 (FGF-10), kera- icles [103].
tinocyte growth factor-2 (KGF-2), has been found to EVs have proposed as an effective vehicle for deliver-
regulate epithelial-mesenchymal interactions that are ing miRNAs, which control above 60% of the mRNAs;
crucial for the development of lung [92]. FGF-10 exerts therefore, transferring them in EVs is of clinical signifi-
a role in lung resident-MSC propagation, mobilization, cance [102]. MSC engineering is one way miRNA could
and the protective effects against acute lung injury [93]. be loaded into EVs and still exert its therapeutic effects