TSG-6 in extracellular vesicles from canine mesenchymal stem/stromal is a major factor in relieving DSS-induced colitis

Abstract

Adipose tissue derived mesenchymal stem/stromal cell (ASC)-derived extracellular vesicles (EV) have been reported to be beneficial against dextran sulfate sodium (DSS)-induced colitis in mice. However, the underlying mechanisms have not been fully elucidated. We hypothesize that the tumor necrosis factor-α-stimulated gene/protein 6 (TSG-6) in EVs is a key factor influencing the alleviation of colitis symptoms. DSS-induced colitis mice (C57BL/6, male, Naïve = 6, Sham = 8, PBS = 8 EV = 8, CTL-EV = 8, TSG-6 depleted EV = 8) were intraperitoneally administered EVs (100 ug/mice) on day 1, 3, and 5; colon tissues were collected on day 10 for histopathological, RT-qPCR, western blot and immunofluorescence analyses. In mice injected with EV, inflammation was alleviated. Indeed, EVs regulated the levels of pro-and anti-inflammatory cytokines, such as TNF-α, IL-1β, IFN-γ, IL-6, and IL-10 in inflamed colons. However, when injected with TSG-6 depleted EV, the degree of inflammatory relief was reduced. Furthermore, TSG-6 in EVs plays a key role in increasing regulatory T cells (Tregs) and polarizing macrophage from M1 to M2 in the colon. In conclusion, this study shows that TSG-6 in EVs is a major factor in the relief of DSS-induced colitis, by increasing the number of Tregs and macrophage polarization from M1 to M2 in the colon.

Therapeutic Potential of Mesenchymal Stromal Cell-Derived Extracellular Vesicles in the Prevention of Organ Injuries Induced by Traumatic Hemorrhagic Shock

“…It was already described that PBMC or macrophage co-culture with adipose-derived MSC-Exo (MSC-derived exosomes) could induce M2 macrophage polarization ( 265 , 268 ). MSC-EVs also inhibited TNF-α and IL-6 production by inflammatory glial cells and limited their activation (loss of CD45 and CD11b expressions) and induction of CCL2, one of the membrane markers of M2 polarization ( 269 ). Finally, bone marrow MSC-EVs could also downregulate the production of IL-23 and IL-22 by macrophages and pro-inflammatory cytokines, inducing Th17 effector T cells.…”

“…However, it was observed that TSG-6 depletion in EVs reduced their immunomodulatory efficacy. TSG-6 in EVs plays a key role in increasing the population of Tregs and for macrophage polarization from M1 to M2 in the colon ( 269 ). Moreover, intraperitoneal injection of MSC-Exo in a mouse model of inflammatory bowel disease indicated a protective role in the intestinal barrier not only by preventing the destruction of tight junctions, therefore decreasing permeability, but also by modulating the responses of Th2 and Th17 cells in the mesenteric lymph nodes.…”

Human Umbilical Cord Mesenchymal Stem Cells-Secreted TSG-6 Is Anti-Inflammatory and Promote Tissue Repair After Spinal Cord Injury

“…(2018) have shown that the exosomes of hucMSCs contain TSG-6, which could reduce lung inflammation with bronchopulmonary dysplasia, reduce brain cell death and hypomyelination reversed in newborn mice. More recently, An et al. (2020) have also reported how TSG-6 within extracellular vesicles derived from mesenchymal stem/stromal cell were essential in modulating exacerbated inflammation to ensure colitis tissue regeneration and repair.…”

Mesenchymal Stem Cell-Derived Extracellular Vesicles: A Potential Therapeutic Strategy for Acute Kidney Injury

“…These processes were mainly mediated by TNF-a-stimulated gene 6 (TSG-6), which regulates inflammation with multiple functions (91)(92)(93). Apart from TSG-6, MSC-EVs also depend on IL-6, IL-10, prostaglandin E2, HGF, and indoleamine2,3dioxygenase to regulate the immune microenvironment (94,95), secreting miRNAs involving miR-155 regulate inflammation on the extracellular environment interact with dendritic cells to regulate endotoxin-induced inflammation (96)(97)(98)(99). In addition, MSC-derived signals mediated by EVs can inhibit the proliferation of natural killer cells, reduce the activity of B lymphocytes, and secrete IL-17 to promote T cell transformation into Treg cells (86,100).…”