Page 60 - Mesenchymal Stem cells, Exosomes and vitamins in the fight aginst COVID

Rogers et al. J Transl Med (2020) 18:203 Page 6 of 19

permeability and restoration of alveolar f uid clearance. MSCs produce extracellular vesicles
T e ef ect was mediated in part by the secretion of KGF Recent studies show that MSCs produce extracellular
which helped restore sodium dependent alveolar f uid vesicles (EVs) that can help ameliorate acute lung injury
transport [109]. Using ex vivo lung perfusion in human [117, 118]. EVs comprise exosomes, microvesicles (MVs)
lungs that had been rejected for transplantation, and apoptotic bodies. MVs form directly by budding from
Genai and colleagues demonstrated that microvesicles the cell membrane and are 100 nm to 1000 nm in size.
derived from human BM-MSCs also increased alveolar T ey are abundant in selectins, integrins, CD-40, phos-
f uid clearance and improved airway and hemodynamic phatidylserine and metalloproteinases. Apoptotic bodies
parameters compared to perfusion alone [110]. Alveo- are fragments of dying cells which form and are released
lar f uid clearance is promoted by keratinocyte growth in the extracellular space by plasma membrane budding
factor (KGF) and KGF repair can be facilitated by MSC during the apoptotic process. T ey are irregular in shape
derived microvesicles that transfer mRNA [111, 112]. and are between 50 and 4000 nm in size. T ey are rich
Fang et al. performed a genome-wide exploratory in DNA and histones [119]. Exosomes are vesicles of
analysis of human alveolar type II cell gene expres- 20–100 nm size with endosomal origin. T e exosomes
sion in response to stimulation with pro-inf ammatory exist intracellularly within multivesicular bodies which
cytokines in the presence or absence of human MSCs. fuse with the cell membrane and then are released into
T ey reported that stimulation of ATII cells with pro- the extracellular space. EVs carry membrane proteins,
inf ammatory cytokines increased expression of inf am- cytosolic proteins, transcription factors, DNA, mRNA,
matory genes and downregulated genes related to rRNA, miRNA and various signal transduction mol-
surfactant function and alveolar f uid clearance. In the ecules. T ey are rich in heat shock proteins, annexins,
presence of MSCs, ATII cells upregulated the genes cytoskeletal proteins, signal transduction proteins and
coding surfactant protein and downregulated genes multivesicular body synthesis proteins. EVs allow inter-
associated with apoptosis which has been linked to cellular information exchange via dif erent mechanisms
ARDS pathogenesis. T e MSCs also induced ATII cells such as internalization, ligand-receptor interaction,
to upregulate genes involved in extracellular matrix secreted factors and fusion-mediated transfer of surface
modif cation and other genes related to injury repair receptors, to name a few. T us, the presence of EVs by
[113]. themselves in health and disease may be detrimental or
Xiang et al. reported the therapeutic potential of benef cial depending on the cell of origin, the cargo they
human menstrual blood-derived MSCs to reduce carry and the information they relay [74].
lipopolysaccharide (LPS)-induced acute lung injury Multiple groups have found a therapeutic advantage
(ALI) inf ammation in mice and promote damaged of administration of MSC-derived MVs by inhalational
repair of lung functions [114]. T ey showed that MSCs or intravascular routes through dif erent mechanisms.
not only improved pulmonary microvascular perme- Zhu et al. showed that intratracheal instillation of MSC-
ability, but also decreased histopathological damage derived MVs in Escherichia coli endotoxin-induced lung
mediated through the downregulation of IL-1β and up- injury reduced extracellular lung water, decreased pul-
regulation of IL-10 expression in bronchoalveolar lavage monary edema and lowered lung protein permeability.
f uid (BALF). Additionally, MSCs improved the activity MVs were also shown to reduce neutrophil inf ux and
of BEAS-2B in human lung epithelial cells and inhibited macrophage inf ammatory protein-2 levels in bronchoal-
LPS induced cell apoptosis. veolar lavage f uid [111]. T e same group demonstrated
Chan et al. compared the extent to which avian inf u- that one of the therapeutic mechanism of MSCs in ALI is
enza A/H5N1 virus and seasonal inf uenza A/H1N1 mediated through increased production of keratinocyte
virus impair alveolar f uid clearance and protein per- growth factor (KGF) [109]. Pretreatment of MSCs with
meability in an in vitro murine model of acute lung KGF siRNA partially eliminated the therapeutic ef ect of
injury [115]. T e alveolar epithelium’s protein perme- MSC-derived MVs. T ey concluded that this therapeu-
ability and f uid clearance were dysregulated by soluble tic ef ect is mediated by the transfer of KGF mRNA from
immune mediators released after infection with avian (A/ MVs to the alveolar epithelium [111].
Hong Kong/483/97, H5N1) but not seasonal (A/Hong MVs derived from human MSCs administered to mice
Kong/54/98, H1N1) inf uenza virus. T ey demonstrated injured with bacterial pneumonia decreased the inf ux
that these ef ects were prevented or reduced by the infu- of inf ammatory cells, cytokines, protein and bacte-
sion of MSCs, which improved survival. Finally, the ria. CD44 receptors mediated the uptake of MVs which
secretion of angiopoietin-1 by MSCs has been shown to is essential for the therapeutic ef ects of MVs [112].
reduce lung protein permeability which acts to stabilize Park et al. tested the therapeutic ef ects of MVs in an
endothelial cells [113, 116]. ex vivo perfused human model of bacterial pneumonia.