Immunomodulatory effects of soluble factors secreted by feline adipose tissue-derived mesenchymal stem cells

Chae, Hyung‐Kyu; Song, Woo‐Jin; Ahn, Ji Yun; Li, Qiang; Lee, Bo‐Yeon; Kweon, Kyeong; Park, Sang-Chul; Youn, Hwa‐Young

doi:10.1016/j.vetimm.2017.07.013

Cited by 20 publications

(20 citation statements)

References 41 publications

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“…PGE2 alters the cytokine secretion profile of the T cell subset to change from a proinflammatory to an anti-inflammatory environment 52,53 . We confirmed the efficacy of ASC in murine-derived macrophage cell lines in inflammatory environments and demonstrated that PGE2 secreted from stem cells is a key factor in polarizing macrophage 12,54 . While further study is needed to assess whether other miRNAs, mRNAs, or proteins also mediate the immunomodulatory effect of the primed cASC-derived EVs, our findings demonstrate that proinflammatory cytokine stimulation was sufficient to induce the cASCs to release EVs containing more potent immunoregulatory factors.…”

Section: Discussionsupporting

confidence: 63%

TNF-α and INF-γ primed canine stem cell-derived extracellular vesicles alleviate experimental murine colitis

Bhang

et al. 2020

Sci Rep

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The inflammatory bowel diseases (IBD) are characterized by relapsing inflammation and immune activation diseases of the gastrointestinal tract. Extracellular vesicles, which elicit similar biological activity to the stem cell themselves, have been used experimentally to treat dextran sulfate sodium (DSS)-induced colitis in murine models though immunosuppressive potential. In this study, we investigated whether the Extracellular vesicles (EVs) obtained by stimulating inflammatory cytokine on canine adipose mesenchymal stem cells (cASC) improved anti-inflammatory and/or immunosuppressive potential of EVs, and/or their ability to alleviate inflammation in colitis. We also explored the correlation between immune cells and the inflammatory repressive effect of primed EVs. Pro-inflammatory cytokines such as TNF-α and ifn-γ increased immunosuppressive protein such as HGF, TSG-6, PGE2 and tGf-β in EVs. Moreover, the anti-inflammatory effect of EVs was improved through pretreatment with inflammatory cytokines. Importantly, EVs obtained from primed stem cells effectively induced macrophage polarization toward an anti-inflammatory M2 phenotype and suppressed activated immunity by enhancing regulatory T cells in inflamed colon in mice. Our results provide a new and effective therapy for the EVs obtained from ASC stimulated with TNF-α and ifn-γ against not only iBD, but also immune-mediated disease.

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Section: Discussionsupporting

confidence: 63%

TNF-α and INF-γ primed canine stem cell-derived extracellular vesicles alleviate experimental murine colitis

Bhang

et al. 2020

Sci Rep

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“…Furthermore, IDO as an antiinflammatory agent has been reported to reduce inflammation in colitis models [49]. In addition, in our previous study, we confirmed the efficacy of adipose-derived stem cells in murinederived macrophage cell lines in inflammatory environments and demonstrated that PGE2 secreted from stem cells is a key factor in polarizing macrophage [50,51]. Moreover, we previous showed that PGE2 secreted feline ASC is a key factor for enhancing regulatory T cell in inflamed colon [52] Although further research on the correlation between these immunomodulatory factors of EV and immune cell regulation is needed, results of the current study confirm that TSG-6-depleted EVs significantly reduce the immunoregulatory ability, which clearly indicates that TSG-6 is a major factor in immune regulation and anti-inflammatory action.…”

Section: Discussionsupporting

confidence: 80%

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

Ryu

et al. 2020

PLoS ONE

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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.

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“…Therefore, MSCs exert strong anti-inflammatory effects, although injected MSCs did not migrate into inflamed tissue in a previous study (Sala et al, 2015). Kang et al and Chae et al also demonstrated that canine and feline MSCs secrete soluble immunomodulatory factors (Chae et al, 2017;Kang et al, 2008). In addition, our previous studies have shown that TSG-6 released from human and canine MSCs ameliorates colitis in mice Song et al, 2017b).…”

Section: Introductionmentioning

confidence: 90%

Canine adipose tissue-derived mesenchymal stem cells pre-treated with TNF-alpha enhance immunomodulatory effects in inflammatory bowel disease in mice

Song

Ryu

et al. 2019

Research in Veterinary Science

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A B S T R A C TCanine inflammatory bowel disease (IBD) is an intractable autoimmune disorder that results in various gastrointestinal and systemic symptoms. Mesenchymal stem cells (MSCs), which release immunomodulatory factors such as tumor necrosis factor-α (TNF-α)-induced gene/protein 6 (TSG-6) and prostaglandin E2 (PGE2), have been suggested as an alternative therapeutic option for IBD treatment in veterinary medicine. Furthermore, although it is known that MSCs pre-treated with pro-inflammatory cytokines show enhanced anti-inflammatory properties via the secretion of soluble factors, the underlying mechanisms of IBD remain unclear. The aim of this study was to demonstrate the therapeutic effects and corresponding mechanisms of canine adipose tissue-derived (cAT)-MSCs stimulated with TNF-α in mouse models of IBD. Mice with dextran sulfate sodium (DSS)-or dinitrobenzene sulfonic acid (DNBS)-induced colitis were injected intraperitoneally with cAT-MSCs pre-treated with TNF-α. Colitis severity was assessed and colon tissues were collected for histopathological, enzyme-linked immunosorbent assay, and flow cytometry analysis. cAT-MSCs stimulated with TNF-α secreted higher concentrations of immunomodulatory factors such as TSG-6 and PGE2, which play a key role in inducing phenotypic alterations in macrophages. Consequently, TNF-α-pre-treated cAT-MSCs further regulated colonic inflammatory cytokines such as interleukin (IL)-1β, IL-6, and IL-10, and ameliorated DSS-or DNBS-induced colitis in mice. Additionally, we demonstrated that M1 macrophages (F4/80 + /iNOS + cells) were decreased in colon tissues from mice treated with TNF-α-pre-treated cAT-MSCs, whereas M2 macrophages (F4/80 + /CD206 + cells) were increased. These results may suggest a new cell-based therapeutic option for treating IBD.

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Immunomodulatory effects of soluble factors secreted by feline adipose tissue-derived mesenchymal stem cells

Cited by 20 publications

References 41 publications

TNF-α and INF-γ primed canine stem cell-derived extracellular vesicles alleviate experimental murine colitis

TNF-α and INF-γ primed canine stem cell-derived extracellular vesicles alleviate experimental murine colitis

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

Canine adipose tissue-derived mesenchymal stem cells pre-treated with TNF-alpha enhance immunomodulatory effects in inflammatory bowel disease in mice

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