Abstract
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.
Highlights
The inflammatory bowel diseases (IBD) are characterized by relapsing inflammation and immune activation diseases of the gastrointestinal tract
We found that conditioned medium (CM) of cultured canine stem cells primed with tumor necrosis factor-alpha (TNF-α) and interferon-gamma (IFN-γ) increase ability to relieve inflammation by pro- and anti-inflammatory cytokine modulation in peripheral blood mononuclear cells and macrophage cell
We investigated the effects of primed Extracellular vesicles (EVs) on dextran sulfate sodium (DSS)-induced colitis
Summary
The inflammatory bowel diseases (IBD) are characterized by relapsing inflammation and immune activation diseases of the gastrointestinal tract. 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. 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. It has been proposed that the predominant way by which stem cells participate is through a paracrine activity[13], and it has been suggested that extracellular vesicle plays a major role in this paracrine activity[6] playing a role in immunoregulation These evidences suggested that by adjusting the culture conditions of stem cells, it is possible to enhance or inhibit certain functions of EVs secreted from stem cells[14,15,16]. No study has evaluated the role of primed ASCs-derived EVs in pre-clinical models relevant for DSS-induced colitis
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