Mesenchymal stem cells-regulated Treg cells suppress colitis-associated colorectal cancer

Abstract

IntroductionPrevious studies have produced controversial results regarding whether mesenchymal stem cells (MSCs) promote or inhibit tumor development. Given the dual role of MSCs in inflammation and cancer, in this study the colitis-associated colorectal cancer (CAC) model was used to examine whether umbilical cord tissue-derived MSCs could prevent neoplasm by inhibiting chronic inflammation.MethodsMSCs were obtained and identified using flow cytometry. Colitis-associated colorectal cancer model was induced using azoxymethane (AOM) and dextran sulfate sodium (DSS) and MSCs were injected intravenously twice. Levels of immune cells in mesenteric lymph node including regulatory T (Treg) cells were detected using flow cytometry. Naïve T cells and Jurkat cells were co-cultured with MSCs and the effect of MSCs on Treg cells differentiation was evaluated.ResultsAfter injection through tail vein, MSCs could migrate to colon and suppress colitis-related neoplasm. This tumor suppressive effect was characterized by longer colon length, decreased tumor numbers and decreased expression of Ki-67. Moreover, MSCs alleviated the pathology of inflammation in the colitis stage of CAC model and inhibited inflammation cytokines both in colon and serum. Furthermore, Treg cells were accumulated in mesenteric lymph node of MSCs-treated mice while the percentage of T helper cells 2 (Th2) and Th17 were not changed. Of note, MSCs secreted transforming growth factor-β (TGF-β) enhanced the induction of Treg cells from naïve T cells. The conditioned medium of MSCs also activated Smad2 signaling, which has been reported to regulate Treg cells.ConclusionsThese results proved that MSCs could migrate to colon tissues and induce the differentiation of Treg cells via Smad2 as so to inhibit the colitis and suppress the development of CAC.

A single administration of human adipose tissue-derived mesenchymal stromal cells (MSC) induces durable and sustained long-term regulation of inflammatory response in experimental colitis

“…Accordingly, these results corroborated previous studies that showed the short-term protective efficacy of MSC on macroscopic and histopathological severity of inflammatory diseases, which has been correlated with the down-regulation of Th1 inflammation [23][24][25][26][27][28]33,37] and the suppression of collagen-reactive T cell-driven production of matrix degrading enzymes [38]. In agreement with the macroscopic findings, we observed that the colon from treated sick animals presented a higher frequency of re-epithelized areas that were repaired earlier.…”

“…Thus, when we analyzed the inflammatory infiltrate of neutrophils by MPO and its correlation with MSC treatment, we observed that these cells were directly related to the colon mucosa inflammation, corroborating previous studies that showed accumulation of neutrophils in the inflammatory site and its reduction after MSC injection [23][24][25]37]. These findings indicated that MSC treatment can revert the local profile of immune response and down-regulate cytokines responsible for the exacerbated inflammation of colon mucosa, in agreement with the reduction of IFN-γ or IL-17 production in the gut of treated mice [25][26][27][28]. In this sense, the recruitment of eosinophils may be directly related to the regression of intestinal inflammation.…”

“…Therefore, although previous studies have already shown the relevance of MSC treatment in variable periods after cellular therapy [25][26][27][28], our findings are pioneering in showing such long-term effects of this modulatory single therapy in colitis, as described previously in other models. This effect was observed in the histopathological results and was also represented by the maintenance of regulation and higher IL-4 levels, together with a reduction of Th17 response after treatment.…”

“…Indeed, several clinical trials have shown short-term positive results in more than 200 nonresponsive patients with refractory IBD, in which MSC promoted a complete clinical remission in approximately 40% and an overall response in approximately 60% (for review, see Grégoire et al [19]). A few studies have showed that MSC injections persistently improved murine colitis by down-regulating Th1 inflammation [25], suppressing T cells [26], inducing T reg differentiation [27] and up-regulating T reg responses [28]. Nevertheless, despite these well-described short-term properties, little is known about long-term MSC effects on IBD.…”

Review article: mesenchymal stromal cell therapy for inflammatory bowel diseases

“…In two studies using a murine model of colitis‐associated tumorigenesis induced by azoxymethane and DSS, MSC therapy even resulted in a significant suppression of colitis‐related neoplasm (reduction in tumour numbers compared to controls), probably because of a reduction of the inflammatory environment. A decreased expression of pro‐inflammatory cytokines and a down‐regulation of STAT3 phosphorylation have been implicated, as well as an enhanced induction of Tregs from naive T cells by MSC‐secreted TGF‐β . Clinical trials with long‐term follow‐up should be performed to definitively assess the safety of MSC therapy.…”