Page 59 - Mesenchymal Stem cells, Exosomes and vitamins in the fight aginst COVID

Rogers et al. J Transl Med (2020) 18:203 Page 5 of 19

animal models. Direct bacterial clearance by MSCs is Keratinocyte growth factor (KGF) is involved in pulmo-
mediated by LL-37 [3] by beta-defensin-2 via the toll-like nary epithelial repair, as shown in a study in which BM-
receptor 4 (TLR-4) signaling pathway [77] and lipocalin-2 MSCs modif ed to express KGF proved ef ective against
[78]. MSCs have been shown to increase the phagocytic bleomycin-induced pulmonary f brosis in a murine
activity of macrophages when reprograming them from model [93–95]. Induced pluripotent stem cell (iPSC)
the pro-inf ammatory to an anti-inf ammatory pheno- conditioned media, known to contain hepatocyte growth
type [79, 80]. factor (HGF), attenuates f brosis and promotes alveolar
epithelium repair [96]. T e administration of UC-MSCs
has also been shown to reduce collagen concentrations
MSCs are anti‑viral in the lung and to inhibit the expression of transforming
MSCs suppress viral replication, viral shedding and growth factor-beta (TGF-β), interferon-gamma (IFN-
virus-induced lung epithelial cell (LEC) damage [4]. γ), macrophage migratory inhibitory factor and tumor
Khatri et al. [4] demonstrated that MSC-derived extracel- necrosis factor-alpha (TNF-α) in a murine model of bleo-
lular vesicles (MSC-EVs) promote both anti-inf amma- mycin-induced acute lung injury [97].
tory and anti-viral properties via transfer of RNAs from
EVs to LECs. In a porcine model of inf uenza viral pneu- MSCs secrete molecules that are mitogenic
monia, they showed that intratracheal administration of and anti‑apoptotic
MSC-EVs signif cantly reduced virus entry and replica- MSCs exert an anti-apoptotic ef ect due to the secretion
tion in LECs. of bioactive factors, such as vascular endothelial growth
Virus shedding in nasal swabs and virus titers in lung
lysate were reduced by 100-fold in the MSC-EV treated factor (VEGF), insulin growth factor (IGF), hepatocyte
growth factor (HGF), neurotrophin-3 and nerve growth
group. Inf uenza virus induced LEC apoptosis and red factor, as well as through mitochondrial and microvesi-
blood cell hemagglutination were signif cantly reduced cle transfer [98–101]. Lung injury is also ameliorated by
by MSC-EVs as well. autophagy which may result from the MSC response to
Inf uenza virus replication is further inhibited by MSC
production of indoleamine 2,3-dioxygenase (IDO) [81] oxidative stress, cytoprotection and phosphoinositide
3-kinase/protein kinase B (P13K/Akt) signaling pathway
and LL37 by viral membrane degradation [82]. IDO has [102–105].
also been shown to suppress viral replication in hepatitis
B, herpes simplex virus (HSV), cytomegalovirus (CMV)
and measles virus [83–86]. Unregulated inf ammation MSCs clear alveolar f uid from the lungs
in inf uenza virus infection leads to extensive lung dam- Alveolar type II (ATII) cells make up approximately 2–5%
age. MSC-EVs are known to decrease production of pro- of the alveolar surface area and have several important
inf ammatory cytokines and chemokines and increase functions. T ey produce surfactant and serve as pro-
production of anti-inf ammatory IL-10 [4]. MSCs inter- genitor cells for the alveolar epithelium. Alveolar f uid
act with immune cells and promote T-regulatory cells is driven by the movement of sodium and chloride ions
(Tregs) which improves inf uenza virus clearance [87, through epithelial transporters down an osmotic gradi-
88]. MSC-EV inhibition of viral replication has also been ent to exit the alveoli and maintain dry airspaces. Patients
demonstrated in hepatitis C virus (HCV) infected f bro- with ARDS have impaired alveolar f uid clearance (AFC)
blasts [89]. which is associated with higher morbidity and mortal-
ity [106]. Multiple studies conf rm that MSC interaction
with sodium and chloride ion channels enhances AFC
MSCs inhibit lung f brosis and scar formation and promotes the resolution of pulmonary edema [107].
Fibroblast and myof broblast deposition are promoted Loy et al. showed that MSCs improved AFC and alveo-
during epithelial tissue repair. Increased cellular matrix lar protein permeability (APP) in an Inf uenza A (H5N1)
protein synthesis leads to low tissue compliance, lung virus-associated acute lung injury. Interestingly, com-
parenchymal scarring and long-term loss of function bined hepatocyte growth factor (HGF) and angiopoietin
[90]. Neutrophil and macrophage recruitment in the 1(Ang-1) restored AFC and APP, but the combination
lung activates prof brotic proteins which promote col- was less ef ective than the MSCs alone [108].
lagen release from f broblasts. Lung tissue obtained Lee et al. studied the therapeutic capacity of human
from patients with f brotic lung diseases contained an BM-MSCs to restore alveolar epithelial f uid trans-
enhanced number of MSCs [91]. Animal models have port and lung f uid balance from acute lung injury in
demonstrated the positive ef ects of MSCs when applied an ex vivo perfused human lung preparation injured
early to ameliorate inf ammation and moderate f brotic by E. coli endotoxin. T ey showed reduced extravas-
lung tissue remodeling [92]. cular lung edema, improved lung endothelial barrier