TSG-6 Secreted by Human Adipose Tissue-derived Mesenchymal Stem Cells Ameliorates DSS-induced colitis by Inducing M2 Macrophage Polarization in Mice

Abstract

Previous studies have revealed that mesenchymal stem cells (MSCs) alleviate inflammatory bowel disease (IBD) by modulating inflammatory cytokines in the inflamed intestine. However, the mechanisms underlying these effects are not completely understood. We sought to investigate the therapeutic effects of human adipose tissue-derived (hAT)-MSCs in an IBD mouse model and to explore the mechanisms of the regulation of inflammation. Dextran sulfate sodium-induced colitis mice were infused with hAT-MSCs intraperitoneally and colon tissues were collected on day 10. hAT-MSCs were shown to induce the expression of M2 macrophage markers and to regulate the expression of pro- and anti-inflammatory cytokines in the colon. Quantitative real time-PCR analyses demonstrated that less than 20 hAT-MSCs, 0.001% of all intraperitoneally injected hAT-MSCs, were detected in the inflamed colon. To investigate the effects of hAT-MSC-secreted factors in vitro, transwell co-culture system was used, demonstrating that tumour necrosis factor-α-induced gene/protein 6 (TSG-6) released by hAT-MSCs induces M2 macrophages. In vivo, hAT-MSCs transfected with TSG-6 small interfering RNA, administered intraperitoneally, were not able to induce M2 macrophage phenotype switch in the inflamed colon and had no significant effects on IBD severity. In conclusion, hAT-MSC-produced TSG-6 can ameliorate IBD by inducing M2 macrophage switch in mice.

Cutaneous Wounds in Mice Lacking Tumor Necrosis Factor-stimulated Gene-6 Exhibit Delayed Closure and an Abnormal Inflammatory Response

“…Although we found no significant difference in the absolute number of macrophages in TSG-6 null versus WT wounds, we did determine that macrophages in TSG-6 null wounds were skewed towards an M1 phenotype. This is in agreement with previous studies showing that and immobilized HC-HA complexes can drive macrophages to a more anti-inflammatory phenotype (Ferrer et al 2017;He et al 2013;Mittal et al 2016), and that TSG-6-producing MSCs can lower proinflammatory marker expression and increase anti-inflammatory M2 macrophages in a colitis model (Song et al 2017). From several lines of evidence, including the fact that M2 macrophages are known to promote tissue repair, and that M1 macrophages are greatly increased in chronic wounds such as diabetic ulcers, it is becoming clear that controlled regulation of macrophage phenotype is critical for proper wound healing (Hesketh et al 2017;Khanna et al 2010;Krzyszczyk et al 2018).…”

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

“…Previous studies have revealed that a high frequency of intraperitoneally infused MSCs aggregated with immune cells in the peritoneal cavity (Sala et al, 2015;Bazhanov et al, 2016). In addition, our previous studies have shown that < 0.5% of intraperitoneally injected MSCs were detected in the heart, lung, liver, spleen, kidney, brain, and colon tissues (Song et al, 2017b;Song et al, 2018). Based on these previous studies, it is tempting to speculate that most of intraperitoneally infused TNF-α-stimulated cAT-MSCs formed aggregates and ameliorated IBD at sites distant from the inflamed colon by releasing soluble factors such as TSG-6 and PGE 2 .…”

“…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).…”

“…Furthermore, administering MSCs as a therapeutic option for IBD in small clinical trials (both in humans and dogs) has also shown considerable promise (Kim et al, 2017;Perez-Merino et al, 2015). Our previous studies have demonstrated that TSG-6 released from human and canine MSCs plays a crucial role in immunomodulation by inducing an M2 macrophage switch Song et al, 2017b). In addition, we have shown that canine MSCs stimulated with TNF-α and IFN-γ released higher concentration of PGE 2 which exert anti-inflammatory effects (Yang et al, 2018).…”

“…Melief et al demonstrated that human MSCs promote the transition of monocytes into CD206 + M2 macrophages, and consequently increase Foxp3 + regulatory T cells (Melief et al, 2013). In addition, recent studies have revealed that soluble factors (such as TSG-6 and PGE 2 ) released from human MSCs could promote the M2 macrophage phenotype and reduce inflammation in mouse models of rheumatoid arthritis, wound healing, and IBD (Shin et al, 2016;Song et al, 2017b;Zhang et al, 2010). Additionally, we previously demonstrated that TSG-6 released from canine MSCs can induce M2 macrophage phenotypic changes in vitro and in vivo .…”