Page 58 - Mesenchymal Stem cells, Exosomes and vitamins in the fight aginst COVID

Rogers et al. J Transl Med (2020) 18:203 Page 4 of 19

in target organs, as they become entrapped in the lung’s [61, 62]. T e ASC’s immunomodulation of dendritic cell
microvasculature [43–45]. Intravenous administration of dif erentiation has been shown to be more ef ective than
MSCs may be useful for patients with multi-organ dis- BM-MSCs [63]. MSCs, when engulfed by immune cells
ease due to the MSC’s ability to home to and act on other such as monocytic cells of predominantly non-classical
injured organs such as the heart, liver and kidney [46]. Ly6C low phenotype, induce phenotypical and functional
changes in monocytes, which subsequently modulate
MSCs are immune‑evasive cells of the adaptive immune system [64, 65].
Culture-expanded MSCs express low levels of MHC class Excessive neutrophil activation in sepsis causes injury
I, and no MHC class II or co-stimulatory molecules B7-1, to lung tissue and other organs. Improvement in organ
B7-2 or CD40 [47]. ASCs express even lower levels of damage associated with sepsis correlates with the reduc-
HLA class-I molecule when compared with BM-MSCs tion of neutrophil inf ltration in target organs. In a
[48]. murine model of sepsis, systemic infusion of allogeneic
ASCs ameliorated clinical and histopathologic evidence
Modulation of the immune system of disease severity and was associated with IL-10-secret-
It is well established that the primary mechanism by ing Treg cells activation [66]. MSCs were also shown to
which MSCs exert their therapeutic ef ects is via secre- inhibit neutrophil oxidative burst, decrease extracellu-
tion of soluble factors known as the secretome. T e MSC lar release of myeloperoxidase and elastase and strongly
secretome is comprised of an array of bioactive mol- attenuate neutrophil mediated damage in an in vivo
ecules that includes cytokines, chemokines, growth fac- model of vasculitis [63, 67, 68].
tors, angiogenic factors and extracellular vesicles. MSCs
may interact directly with immune cells and execute par- Production of anti‑inf ammatory molecules
acrine modulation of the immune response by the release T e administration of MSCs has demonstrated anti-
of cytokines such as IL-10, IL-1RA, TGF-β, and the pro- inf ammatory ef ects in many acute lung injury models
duction of indoleamine 2,3 dioxygenase (IDO) and nitric [69–72]. MSCs shift inf ammation from an overwhelm-
oxide [49]. ing release of pro-inf ammatory cytokines including
T ese mechanisms modulate the proliferation and acti- IL-1β, IL-6, MCP-1, MIP-2, CXCL-1, CXCL-2, TNF-β,
vation of naïve and ef ector T cells, natural killer (NK) IL-12, IL-17 or type II IFN-γ and proteases like MMP-
cells and mononuclear cells towards an anti-inf amma- 2, MMP-9 and MMP-12 to an anti-inf ammatory sta-
tory phenotype. Modulation of T cell function includes tus. Released anti-inf ammatory cytokines include IL-4,
the inhibition of the T 17 response, the induction of IL-10, TGF- α, CCL18, prostaglandin E2, IDO, nitric
regulatory T cells, and the shift from a T 1 to the T 2 oxide and lipoxin A4. T is shift promotes the resolution
cell phenotype. T is process is regulated by anti-inf am- of inf ammation and tissue repair [73, 74].
matory cytokines, including IL-10 and TGF-β, growth MSCs shift the phenotype and function of anti-
factors such as HGF, and additional soluble factors like gen-presenting cells, including dendritic cells, B lym-
PGE2 and the inhibition of cytokines like IL-4 and IL-13 phocytes and macrophages and prevent neutrophil
[50, 51]. extracellular trap formation [75]. T e phenotype switch
Improved outcomes after MSC infusions in multiple in macrophages leads to a return from the M1 state to the
medical conditions have been primarily attributed to “anti-inf ammatory” M2 state. T is switch is induced by
the MSC-based production of paracrine factors which the inf ammatory milieu of bacterial infection which fos-
interact with immune cells resulting eventually in immu- ters inf ammation by the release of pro-inf ammatory fac-
nomodulation [52–55]. Several studies have demon- tors, including cytokines and proteolytic enzymes.
strated that MSCs regulate the activity of both the innate In the liver, MSCs regulate the NLRP3 inf ammasome
and adaptive immune response via direct cell–cell con- which regulates the activation of capsase-1 and the sub-
tact and trophic factors. COVID-19 patients have been sequent inf ammatory response to infectious microbes
shown to possess reduced regulatory T cells counts, and molecules in Kupf er cells via secretion of PGE2. T is
especially in severe cases [56]. MSCs, and in particu- leads to increased IL-10 production by the Kupf er cells
lar, ASCs increase the generation of regulatory T cells and alleviation of the inf ammatory response and organ
(Treg) [57–59]. ASCs have been shown to promote the dysfunction [76].
development of Tregs more ef ectively than BM-MSCs
or Wharton jelly-derived MSCs (WJ-MSC) [60]. MSCs MSCs are anti‑bacterial and promote macrophage removal
also demonstrate inhibition of the proliferation, activa- of bacteria
tion and maturation of CD19 B cells, CD4 T 1 cells, MSCs possess innate antimicrobial properties, which
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CD8 T cells, macrophages, monocytes and neutrophils have been demonstrated both in vitro and in small
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