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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 protect mice against the development of DSS-induced colitis on day 33. Colons were excised for macroscopic observation (A) and assessment of colonic length (B). (C) The changes in body weight were calculated based on initial body weight. (D) The clinical disease score of colitis, which includes stool status, fecal blood, length of colon and weight loss, was used to evaluate the therapeutic effect of MSCs. (E) Colon sections from mice with different treatments were examined using H & E staining. (F) Histology scores were derived from microscopic analysis of longitudinal colon sections from each mouse. Values are expressed as means ± SEM. *P <0.05, or **P <0.01. DSS, dextran sulfate sodium; MSCs mesenchymal stem cells; SEM, standard error of the mean.
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Fig3: MSCs protect mice against the development of DSS-induced colitis on day 33. Colons were excised for macroscopic observation (A) and assessment of colonic length (B). (C) The changes in body weight were calculated based on initial body weight. (D) The clinical disease score of colitis, which includes stool status, fecal blood, length of colon and weight loss, was used to evaluate the therapeutic effect of MSCs. (E) Colon sections from mice with different treatments were examined using H & E staining. (F) Histology scores were derived from microscopic analysis of longitudinal colon sections from each mouse. Values are expressed as means ± SEM. *P <0.05, or **P <0.01. DSS, dextran sulfate sodium; MSCs mesenchymal stem cells; SEM, standard error of the mean.

Mentions: To induce colorectal cancer successfully, the chronic colitis should emerge first in three cycle inductions. It is now commonly accepted that inflammation contributes to the initiation, promotion, and progression of tumor development. To confirm that MSCs inhibit carcinogenesis through inhibition of colonic inflammation, half of the mice in the tumor group were sacrificed on day 32. As shown in Figures 3A to D, MSC treatment significantly alleviated chronic inflammation with improved clinical scores. MSC treatment also improved colitis characteristics with increased body weight (P <0.05) and colon length (P <0.05). Moreover, histological examination of the colon in mice without MSCs showed patchy ulceration, epithelial cell loss, reduction of the density of tubular glands, focal loss of crypts, inflammatory cell infiltrates and transmural inflammation involving all layers of the bowel wall. Expectedly, these colitis characteristics were reversed after MSC treatment (Figures 3E and F, P <0.05). These results consistently demonstrated that during the development of CAC, MSCs had a protective function on DSS-induced colitis by inhibiting excessive inflammation in colon tissues.Figure 3


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 protect mice against the development of DSS-induced colitis on day 33. Colons were excised for macroscopic observation (A) and assessment of colonic length (B). (C) The changes in body weight were calculated based on initial body weight. (D) The clinical disease score of colitis, which includes stool status, fecal blood, length of colon and weight loss, was used to evaluate the therapeutic effect of MSCs. (E) Colon sections from mice with different treatments were examined using H & E staining. (F) Histology scores were derived from microscopic analysis of longitudinal colon sections from each mouse. Values are expressed as means ± SEM. *P <0.05, or **P <0.01. DSS, dextran sulfate sodium; 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

Fig3: MSCs protect mice against the development of DSS-induced colitis on day 33. Colons were excised for macroscopic observation (A) and assessment of colonic length (B). (C) The changes in body weight were calculated based on initial body weight. (D) The clinical disease score of colitis, which includes stool status, fecal blood, length of colon and weight loss, was used to evaluate the therapeutic effect of MSCs. (E) Colon sections from mice with different treatments were examined using H & E staining. (F) Histology scores were derived from microscopic analysis of longitudinal colon sections from each mouse. Values are expressed as means ± SEM. *P <0.05, or **P <0.01. DSS, dextran sulfate sodium; MSCs mesenchymal stem cells; SEM, standard error of the mean.
Mentions: To induce colorectal cancer successfully, the chronic colitis should emerge first in three cycle inductions. It is now commonly accepted that inflammation contributes to the initiation, promotion, and progression of tumor development. To confirm that MSCs inhibit carcinogenesis through inhibition of colonic inflammation, half of the mice in the tumor group were sacrificed on day 32. As shown in Figures 3A to D, MSC treatment significantly alleviated chronic inflammation with improved clinical scores. MSC treatment also improved colitis characteristics with increased body weight (P <0.05) and colon length (P <0.05). Moreover, histological examination of the colon in mice without MSCs showed patchy ulceration, epithelial cell loss, reduction of the density of tubular glands, focal loss of crypts, inflammatory cell infiltrates and transmural inflammation involving all layers of the bowel wall. Expectedly, these colitis characteristics were reversed after MSC treatment (Figures 3E and F, P <0.05). These results consistently demonstrated that during the development of CAC, MSCs had a protective function on DSS-induced colitis by inhibiting excessive inflammation in colon tissues.Figure 3

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