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

Tang RJ, Shen SN, Zhao XY, Nie YZ, Xu YJ, Ren J, Lv MM, Hou YY, Wang TT - Stem Cell Res Ther (2015)

Bottom Line: Colitis-associated colorectal cancer model was induced using azoxymethane (AOM) and dextran sulfate sodium (DSS) and MSCs were injected intravenously twice.Naïve T cells and Jurkat cells were co-cultured with MSCs and the effect of MSCs on Treg cells differentiation was evaluated.These 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.

View Article: PubMed Central - PubMed

Affiliation: The State Key Laboratory of Pharmaceutical Biotechnology, Division of Immunology, Medical School, Nanjing University, Nanjing, 210093, China. trjtrjtrj@163.com.

ABSTRACT

Introduction: Previous 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.

Methods: MSCs 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.

Results: After 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.

Conclusions: These 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.

No MeSH data available.


Related in: MedlinePlus

MSCs suppressed the expression of inflammatory cytokines. (A) Bio-Plex Assay was used to analyze cytokine changes in mice plasma, including IL-1α, IL-1β, IL-3, IL-4, IL-5, IL-6, IL-12, IL-13, G-CSF and RANTES. (B) The expression levels of colonic inflammatory cytokines (IL-1β, IL-6 and TNF-α) from different groups were evaluated by Q-PCR. (C) The expression of p-P65 examined by immunohistochemistry staining comparing the colons in the treated and untreated groups. Values are expressed as means ± SEM. *P <0.05, or **P <0.01. MSCs, mesenchymal stem cells; SEM, standard error of the mean.
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Fig4: MSCs suppressed the expression of inflammatory cytokines. (A) Bio-Plex Assay was used to analyze cytokine changes in mice plasma, including IL-1α, IL-1β, IL-3, IL-4, IL-5, IL-6, IL-12, IL-13, G-CSF and RANTES. (B) The expression levels of colonic inflammatory cytokines (IL-1β, IL-6 and TNF-α) from different groups were evaluated by Q-PCR. (C) The expression of p-P65 examined by immunohistochemistry staining comparing the colons in the treated and untreated groups. Values are expressed as means ± SEM. *P <0.05, or **P <0.01. MSCs, mesenchymal stem cells; SEM, standard error of the mean.

Mentions: Cytokine levels are critical evidence to show the effect of immune cells on CAC growth. In order to test the effect of MSCs on levels of inflammatory cytokines, serum from different groups of mice was collected and cytokine levels were detected using a Bio-Plex cytokine kit. Compared with the untreated group, inflammatory cytokines, including IL-1α, IL-1β, IL-5, IL-6 and IL-12, were decreased significantly after treatment with MSCs (Figure 4A, P <0.05).Figure 4


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

Tang RJ, Shen SN, Zhao XY, Nie YZ, Xu YJ, Ren J, Lv MM, Hou YY, Wang TT - Stem Cell Res Ther (2015)

MSCs suppressed the expression of inflammatory cytokines. (A) Bio-Plex Assay was used to analyze cytokine changes in mice plasma, including IL-1α, IL-1β, IL-3, IL-4, IL-5, IL-6, IL-12, IL-13, G-CSF and RANTES. (B) The expression levels of colonic inflammatory cytokines (IL-1β, IL-6 and TNF-α) from different groups were evaluated by Q-PCR. (C) The expression of p-P65 examined by immunohistochemistry staining comparing the colons in the treated and untreated groups. Values are expressed as means ± SEM. *P <0.05, or **P <0.01. MSCs, mesenchymal stem cells; SEM, standard error of the mean.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4414289&req=5

Fig4: MSCs suppressed the expression of inflammatory cytokines. (A) Bio-Plex Assay was used to analyze cytokine changes in mice plasma, including IL-1α, IL-1β, IL-3, IL-4, IL-5, IL-6, IL-12, IL-13, G-CSF and RANTES. (B) The expression levels of colonic inflammatory cytokines (IL-1β, IL-6 and TNF-α) from different groups were evaluated by Q-PCR. (C) The expression of p-P65 examined by immunohistochemistry staining comparing the colons in the treated and untreated groups. Values are expressed as means ± SEM. *P <0.05, or **P <0.01. MSCs, mesenchymal stem cells; SEM, standard error of the mean.
Mentions: Cytokine levels are critical evidence to show the effect of immune cells on CAC growth. In order to test the effect of MSCs on levels of inflammatory cytokines, serum from different groups of mice was collected and cytokine levels were detected using a Bio-Plex cytokine kit. Compared with the untreated group, inflammatory cytokines, including IL-1α, IL-1β, IL-5, IL-6 and IL-12, were decreased significantly after treatment with MSCs (Figure 4A, P <0.05).Figure 4

Bottom Line: Colitis-associated colorectal cancer model was induced using azoxymethane (AOM) and dextran sulfate sodium (DSS) and MSCs were injected intravenously twice.Naïve T cells and Jurkat cells were co-cultured with MSCs and the effect of MSCs on Treg cells differentiation was evaluated.These 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.

View Article: PubMed Central - PubMed

Affiliation: The State Key Laboratory of Pharmaceutical Biotechnology, Division of Immunology, Medical School, Nanjing University, Nanjing, 210093, China. trjtrjtrj@163.com.

ABSTRACT

Introduction: Previous 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.

Methods: MSCs 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.

Results: After 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.

Conclusions: These 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.

No MeSH data available.


Related in: MedlinePlus