Page 28 - Mesenchymal Stem cells, Exosomes and vitamins in the fight aginst COVID

Al-Khawaga and Abdelalim Stem Cell Research & Therapy (2020) 11:437 Page 9 of 33

[104–113]. There is a lack of a consensus on miRNA sig- PGE2 changes the macrophage polarization from M1 to
nature among MSC-EVs from various sources [114]. M2 [144], IL10 decreases the recruitment of the neutro-
However, the targeted pathways include Wnt signaling, phils into the lung [145], and IDO enhances pulmonary
antifibrotic, mitochondrial fission, cell proliferation, cell antimicrobial activity [146]. Furthermore, the propaga-
survival, and apoptosis [115]. Reports showed that the tion, differentiation, and chemotactic features of B cells
MSC-EV-mediated delivery of miRNAs in animal are hindered by MSCs as well [147] (Fig. 2). MSCs can
models have defined several key target proteins like further enhance restoration of capillary barrier, restore
TGF-β receptor 1, Dynamin-related protein 1(DRP1), alveolar ATP [141], where the secreted growth factors
Methyl-CpG-binding protein 2 (Mecp2), PTEN, sema- KGF, VEGF, and HGF, can exert a protective effect on
phorin 3A (sema3A), stat3, Cyclin G1, IGF1R, and the alveolar cells [148]. In ALI models, the KGF mRNA
P4HA1, NLRP3, and Bcl-2 [9, 104–113] (Table 1). has been involved in the immunomodulation noticed
Among the targeted proteins, Sema3A has been found with MSC-EV treatment [126, 129]. MSC anti-bacterial
to induce sepsis-triggered cytokine storm through an effect is further demonstrated in inhibition of bacterial
interaction with Plexin-A4 and Toll-like receptors growth [57]. Several preclinical studies examined the
(TLRs) [116]. Stat3 is another targeted protein, a key up- therapeutic effects of MSCs and MSC-derived EVs in
stream stimulator of inflammatory pathways during sep- animal models of ALI, ARDS, and other lung inflamma-
sis [117]. Finally, EVs act as biological regulators that tory conditions [126–143, 149–151] (Table 2). These
can promote changes in their targets through targeted studies showed a significant decrease in the inflamma-
pathways. The cargo of the EVs is enriched with miR- tory reactions, improved edema clearance, and restored
NAs and other transcripts that act as regulators of the epithelial damage (Table 2). A preclinical study reported
immune system [118, 119]. Therefore, EVs are attractive that the intratracheal administration of MSCs increases
tools for clinical applications as immunosuppressants, the accessibility of MSCs to both the alveolar epithelium
vaccines, or activators of differentiation and repair pro- and the pulmonary endothelium [152], where MSCs
cesses [120]. demonstrate reduction in endotoxin-induced injury to
explanted human lungs [153].
MSCs and their exosomes as potential therapies MSC-derived exosomes are a multitargeted biologic
for COVID-19 agent, which can reduce the cytokine storm and reverse
MSCs have been well described in ALI and ARDS. It ex- the inhibition of host anti-viral defenses associated with
erts its function via targeting both infectious, inflamma- COVID-19 [154]. The functions of the MSC-derived
tory, and endothelial factors. MSCs can release KGF2, exosomes have been studied in in vitro and in vivo
PGE2, GM-CSF, IL-6, and IL-13 to facilitate phagocyt- models. EVs collected from the conditioned medium of
osis (Figs. 2 and 3). In addition, multiple clinical studies BM-MSCs have been used to treat ARDS in a mouse
[121–125] investigated the effect and mechanism of model. The results showed that EVs have a similar effect
MSCs and MSC-EVs on lung injuries caused by different as MSCs in reducing the inflammation and edema in the
reasons (Table 2). MSCs and their secreted secretome lung [126]. The effect of MSCs on macrophage modula-
exert an immunomodulatory, anti-inflammatory, anti- tion in ARDS mouse models has been mainly found due
apoptotic, and anti-fibrotic functions in ALI and ARDS. to the effect of EVs [127]. Treating mouse alveolar

Table 1 Studies demonstrating the MSC-EV-mediated transfer of miRNAs in animal models
miRNA transferred Target proteins Function Reference
miR-let7c TGF-β receptor 1 Anti-fibrotic [104]
miR-30 Dynamin-related protein 1 Regulate mitochondrial fission [105]
(DRP1)
miR-22 Methyl-CpG-binding protein 2 (Mecp2) Anti-fibrotic [106]
miR-19a PTEN Cell survival signaling pathway [107]
miR-223 Semaphorin 3A (Sema3A) and Stat3 Anti-apoptotic and antiinflammatory [108]
miR-122 Cyclin G1, IGF1R, and P4HA1 Anti-proliferative and antifibrotic [109]
miR-223 NLRP3 Anti-inflammatory: decrease pytoptosis and IL-1β [110]
miR-181 Bcl-2 and Stat3 Anti-fibrotic and activated autophagy [111]
miR-133 RhoA and connective tissue growth factor Enhanced plasticity [112]
miR-17-92 PTEN Cell survival signaling pathway [113]
IGF1R insulin-like growth factor receptor 1, P4HA1 prolyl 4-hydroxylase alpha 1, NLRP3 NLR pyrin domain-containing 3, RhoA homolog gene family member A, BCL-
2 B cell lymphoma 2 family