Page 26 - Mesenchymal Stem cells, Exosomes and vitamins in the fight aginst COVID

Al-Khawaga and Abdelalim Stem Cell Research & Therapy (2020) 11:437 Page 7 of 33

volume of about 0.4–0.5 ml of packed cells can be gener- secrete high levels of pro-inflammatory cytokines,
ated [53]. The MSC isolation from different tissues, such while M2 macrophages secrete lower levels of pro-
as BM and adipose tissue and their re-implantation at inflammatory cytokines, exhibit tissue repair, and en-
other sites highlight their ability to repair tissues in vivo. hance the resolution of inflammation [66]. Imbalance
However, this process clearly diminishes in aging popu- between M1- and M2- activities can lead to continu-
lation compared to younger adults [54]. In addition, ous inflammation and hinders the normal repair
MSCs could be generated in vitro in large number from process, both contributing to impaired tissue repair
human pluripotent stem cells (hPSCs) [55, 56], which [67]. MSCs enhance tissue repair and regeneration by
showed a lower immunogenicity in comparison to adult modulating the immune response, acting as sensors
sources [49]. and switchers of inflammation, rather than by re-
MSCs have been extensively examined for their thera- placing damaged cells. This is largely attributed to the
peutic capacity in regenerative medicine, because of their secretion of growth factors; among the immunoregu-
ability to home to sites of inflammation and damaged latory factors are prostaglandin E2 (PGE2) and IL-6
tissue, ultimately serving as a source of growth and that help in transitioning macrophages toward M2
trophic factors and regenerative molecules. The potential phenotype [68, 69](Fig. 2). Further, the classical pro-
therapeutic effect of MSCs is based on their low im- inflammatory cytokines produced at the acute stage of
munogenicity, their immunomodulatory characteristics, inflammation, such as IFN-γ,TNF-α,orIL-1β en-
and their ability to secrete growth factors, as well as hances the paracrine effects of MSCs exerted on mac-
anti-microbial peptides [57]. MSCs administered system- rophages [70, 71].
ically tend to migrate to the injury region to promote In order to stimulate the MSC immunosuppressive ef-
functional recovery [58]. MSCs can also extravasate from fect, threshold levels of inflammatory factors are re-
the blood vessels, just like immune cells, via the expres- quired. Insufficient MSC activation can lead to an
sion of cell surface adhesion molecules. Migration of increase in the inflammation [72]. Recently, it has been
MSCs occur in response to chemokines binding to cog- shown that IL-10 alone is insufficient to enhance MSC
nate receptors present on their cell surface [59] and re- immunomodulation, rather enhances the priming influ-
sult in the stimulation of matrix metalloproteinases ence of TNF-α, indicating that MSC activation by IL-10
degrading the basal membrane and allowing subsequent is dependent on TNF-α [64]. MSCs further decrease
extravasation [60]. By displaying a coordinated rolling, TNF-α secretion via PGE2 but not IL-6, supporting the
MSCs contact the endothelial cells in a P-selectin- and concept that MSC immunomodulatory potential is
vascular cell-adhesion molecule 1 (VCAM1)-dependent highly correlated to the release of PGE2 [64].
manner [61]. Guided by chemotactic signals, MSCs mi- Among the other MSC-derived molecules shown to
grate through the interstitium to the injured area. An in- exert an immunoregulatory functions are transforming
crease in the MSC migration capacity toward growth factor beta (TGF-β), hepatocyte growth factor
chemokines is achieved via the upregulation of their re- (HGF), and indoleamine 2,3-dioxygenase (IDO) [73]
ceptors, CCR2, CCR3, and CCR4. Also, interleukin (IL)- (Fig. 2). TGF-β secreted by MSCs could shift
8, an inflammatory chemokine, may induce migration of lipopolysaccharide-activated macrophage polarization to-
MSCs to injured areas [62, 63]. ward the M2-phenotype, decrease inflammatory reac-
tions, and enhance the phagocytic activity through the
Immunoregulatory functions of MSCs Akt/FoxO1 pathway [74], while HGFs modulate IL-10
One of the major therapeutic characteristics of MSCs production in monocytes via the ERK1/2 pathway [75].
is their immunomodulatory role, including a network MSC IDO activity is involved in the differentiation of
of cytokines and cell-cell interactions. Interestingly, monocytes into IL-10-secreting M2 immunosuppressive
+
+
MSCs only exert its immunoregulatory capacity after macrophages (CD14 /CD206 )[71]. These processes de-
receiving the activation signals from the inflammatory crease immune cell maturation and activation, in
milieu; therefore, MSC’s immunoregulatory capacity is addition to enhancing the differentiation of T cells into
not constitutive, rather is driven by “licensing” regulatory T cells (Tregs) [52].
process [64]. Previous studies showed that the macro- The immunoregulatory effects of MSCs is highlighted
phages play an essential role during wound healing; by the ability of BM-MSCs to suppress T cell prolifera-
thus, they have emerged as key candidate targets in tion [76, 77] and suppress the conversion of monocytes
+
therapeutic tissue regeneration approaches [64, 65]. and CD34 hematopoietic progenitor cells into dendritic
Macrophages exhibit functional repolarization as tis- cells (DCs) in vitro [78–81]. Mature DCs cultured with
sue repair progresses, shifting from the pro- MSCs have reduced production of IL-12 and MHC class
inflammatory or M1-phenotype to an anti- II molecules, CD11c, CD83, though hindering the DC
inflammatory or M2-phenotype. M1 macrophages antigen-presenting function [78–81].