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.
Highlights
Recent studies have demonstrated that mesenchymal stem cells (MSCs) show anti-inflammatory effects and can alleviate the symptoms in various inflammatory disease models, including rheumatoid arthritis, peritonitis, and pancreatitis, as well as IBD6–9
Intraperitoneal injection of human adipose tissue-derived (hAT)-MSCs was shown to lead to a significant reduction in body weight loss, in comparison with that measured in mice injected with the phosphate-buffered saline (PBS) from day 7 (Fig. 1a)
On day 10, the disease activity index (DAI) of mice treated with hAT-MSCs was significantly decreased, in comparison with that in the mice treated with PBS (Fig. 1b)
Summary
Recent studies have demonstrated that mesenchymal stem cells (MSCs) show anti-inflammatory effects and can alleviate the symptoms in various inflammatory disease models, including rheumatoid arthritis, peritonitis, and pancreatitis, as well as IBD6–9. Of the best-known secretory factors responsible for anti-inflammatory activity, and recently, it was demonstrated that it plays crucial roles in the regulation of inflammatory responses in IBD, peritonitis, myocardial infarction, lung injury, corneal injury, and skin wound healing[12,13,14,15,16,17]. Recent in vitro and inflammation-induced animal model studies demonstrated that MSCs can induce M1 to M2 macrophage phenotypic switch[22,23,24], but the mechanisms underlying this process are not clearly understood. We assessed the effects of human adipose tissue-derived (hAT)-MSCs on a dextran sulfate sodium (DSS)-induced colitis model in mice, together with the effect on phenotypic switch in macrophages. We aimed to elucidate the mechanisms underlying these processes
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