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

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.

Extracellular Vesicles from Thapsigargin-Treated Mesenchymal Stem Cells Ameliorated Experimental Colitis via Enhanced Immunomodulatory Properties

“…Previous studies have shown that Treg and/or macrophages play an important role in IBD pathogenesis by regulating the function of neutrophils, dendritic cells, and other inflammatory cells [ 51 , 52 ]. In line with previous reports [ 19 , 20 , 53 ], our data indicated that MSC EVs could modulate macrophage polarization from M1-type to M2-type in the colons of DSS-colitic mice based on significantly enhanced Arg-1 and CD206 expression in colon macrophages. Furthermore, significantly up-regulated Tregs in TSG-EV treated colitic mice possibly played an important role in preventing intestinal inflammation by inhibiting the activity of Th1 and Th17 [ 36 , 54 , 55 ] or through interaction with macrophages [ 56 , 57 ].…”

“…It has been reported that MSC EVs can mediate immunomodulatory effects through induction of regulatory T cells (Tregs) and M2-type macrophage polarization [ 20 , 33 ]. Thus, we investigated the effect of TSG-EV on specific T cell subsets.…”

“…In addition, UC-MSC-derived EVs have been shown to reduce colitis in mice by repolarizing macrophages to an anti-inflammatory M2 phenotype [ 19 ]. An et al reported that TNFα- and IFNγ-primed MSC-derived EVs effectively induce macrophage polarization with an anti-inflammatory M2 phenotype and suppress activated immunity by enhancing regulatory T cells in the inflamed mouse colon [ 20 ]. Taken together, these findings are evidence that EVs secreted from MSCs elicit therapeutic effects of MSCs and may be further enhanced by pretreatment and conditioning.…”

Graphene oxide aggravated dextran sulfate sodium-induced colitis through intestinal epithelial cells autophagy dysfunction

“…To date, IBD is still an incurable disease, and more and more dangerous factors that may cause adverse effects on IBD patients have been found. Along with the development of new technology and increased presence of materials, a large number of scientific experiments have been conducted to improve the conditions of IBD patients (Corbo et al, 2017;An et al, 2020). Cure and prevention are two important aspects of the process of disease treatment.…”

Extracellular Vesicles in Cell Biology and Medicine

“…Other Articles included in the Collection have explored the use of EVs in therapeutics. For the treatment of immune-related diseases, the application of an inflammatory stimulus is shown to improve the anti-inflammatory and/or immunosuppressive potential of EVs secreted by adipose mesenchymal stem cells 5 . Cytoprotection of stressed cardiomyocytes through the use of EVs derived from mesenchymal stromal cells 6 , and the prevention of glucocorticoid-induced osteoporosis -through the suppression of osteoblasts' ferroptic pathway -by EVs extracted from bone marrow-derived endothelial progenitor 7 , were also demonstrated.…”