Regulatory effect of rat bone marrow mesenchymal stem cells on Treg/Th17 immune balance in vitro

Wang,Kai; Shi,Yan‑Jun; Song,Zhuo‑Lun; Wu,Bin; Zhou,Chun‑Lei; Liu,Wei; Gao,Wei

doi:10.3892/mmr.2020.11019

Regulatory effect of rat bone marrow mesenchymal stem cells on Treg/Th17 immune balance in vitro

Authors:
- Kai Wang
- Yan‑Jun Shi
- Zhuo‑Lun Song
- Bin Wu
- Chun‑Lei Zhou
- Wei Liu
- Wei Gao
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Affiliations: Department of Transplant Surgery, Tianjin First Central Hospital, Tianjin 300192, P.R. China, Hillman Center for Pediatric Transplantation, Department of Transplant Surgery, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, PA 15224, USA, Clinical Laboratory, Tianjin First Central Hospital, Tianjin 300192, P.R. China, Blood Transfusion Department, Tianjin First Central Hospital, Tianjin 300192, P.R. China
Published online on: March 11, 2020 https://doi.org/10.3892/mmr.2020.11019
Pages: 2123-2130
Copyright: © Wang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Bone marrow mesenchymal stem cells (BM‑MSCs) regulate the balance between regulatory T cells (Tregs) and T helper 17 (Th17) cells. However, the role of different factors on BM‑MSCs‑mediated regulation of the Treg/Th17 balance is unknown. BM‑MSCs and CD4+ T lymphocytes were co‑cultured with various treatments. The ratio of Treg/Th17 cells was calculated and the expression of different cytokines was measured. BM‑MSCs were found to have a proliferative effect on Th17 cells at a basal concentration and at a 2‑fold increase in the number of BM‑MSCs. However, when the number of BM‑MSCs used was increased 4‑fold, they had an inhibitory effect on the Th17 cells. The effect of BM‑MSCs on Tregs was inhibited by the addition of tacrolimus but not rapamycin. The effect of BM‑MSCs on Th17 cells was inhibited by rapamycin. Additionally, the effect of BM‑MSCs on Tregs were inhibited by the addition of a transforming growth factor‑β (TGF‑β) blocker, whereas these TGF‑β‑blockers had no effect on Th17 cells. Addition of an interleukin (IL)‑2 blocker reduced the proportion of Th17 cells when co‑cultured with a high number of MSCs compared with the low concentration group and the proportion of Treg cells was significantly decreased when cells were treated with an IL‑2 blocker compared with the control group. Together, these results showed the varying effects of MSCs on the ratio of Treg/Th17, its dependence on the number of MSCs and the effects of cytokines in inducing these changes in the balance.

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1	Mohammadpour H, Pourfathollah AA, Zarif MN and Tahoori MT: TNF-α modulates the immunosuppressive effects of MSCs on dendritic cells and T cells. Int Immunopharmacol. 28:1009–1017. 2015. View Article : Google Scholar : PubMed/NCBI
2	Romano M, Fanelli G, Tan N, Nova-Lamperti E, McGregor R, Lechler RI, Lombardi G and Scottà C: Expanded regulatory T cells induce alternatively activated monocytes with a reduced capacity to expand T helper-17 cells. Front Immunol. 9:16252018. View Article : Google Scholar : PubMed/NCBI
3	Özdemir AT, Özgül Özdemir RB, Kırmaz C, Sarıboyacı AE, Ünal Halbutoğlları ZS, Özel C and Karaöz E: The paracrine immunomodulatory interactions between the human dental pulp derived mesenchymal stem cells and CD4 T cell subsets. Cell Immunol. 310:108–115. 2016. View Article : Google Scholar : PubMed/NCBI
4	Heidt S, Segundo DS, Chadha R and Wood KJ: The impact of Th17 cells on transplant rejection and the induction of tolerance. Curr Opin Organ Transplant. 15:456–461. 2010. View Article : Google Scholar : PubMed/NCBI
5	Sun Z, Li T, Wen H, Wang H, Ji W and Ma W: Immunological effect induced by mesenchymal stem cells in a rat liver transplantation model. Exp Ther Med. 10:401–406. 2015. View Article : Google Scholar : PubMed/NCBI
6	Gharibi T, Ahmadi M, Seyfizadeh N, Jadidi-Niaragh F and Yousefi M: Immunomodulatory characteristics of mesenchymal stem cells and their role in the treatment of multiple sclerosis. Cell Immunol. 293:113–121. 2015. View Article : Google Scholar : PubMed/NCBI
7	Kim N and Cho SG: Overcoming immunoregulatory plasticity of mesenchymal stem cells for accelerated clinical applications. Int J Hematol. 103:129–137. 2016. View Article : Google Scholar : PubMed/NCBI
8	Zhou Y, Yang X, Zhang H and Jiang J: The roles of T helper type 17/regulatory T cells in acute rejection after liver transplantation in rats. Transplantation. 99:1126–1131. 2015. View Article : Google Scholar : PubMed/NCBI
9	Liu X, Ren S, Qu X, Ge C, Cheng K and Zhao RC: Mesenchymal stem cells inhibit Th17 cells differentiation via IFN-ү-mediated SOCS3 activation. Immunol Res. 61:219–229. 2015. View Article : Google Scholar : PubMed/NCBI
10	Tang J, Yang R, Lv L, Yao A, Pu L, Yin A, Li X, Yu Y, Nyberg SL and Wang X: Transforming growth factor-β-expressing mesenchymal stem cells induce local tolerance in a rat liver transplantation model of acute rejection. Stem Cells. 34:2681–2692. 2016. View Article : Google Scholar : PubMed/NCBI
11	Rozenberg A, Rezk A, Boivin MN, Darlington PJ, Nyirenda M, Li R, Jalili F, Winer R, Artsy EA, Uccelli A, et al: Human mesenchymal stem cells impact Th17 and Th1 responses through a prostaglandin E2 and myeloid-dependent mechanism. Stem Cells Transl Med. 5:1506–1514. 2016. View Article : Google Scholar : PubMed/NCBI
12	Rashedi I, Gómez-Aristizábal A, Wang XH, Viswanathan S and Keating A: TLR3 or TLR4 activation enhances mesenchymal stromal cell-mediated treg induction via notch signaling. Stem Cells. 35:265–275. 2017. View Article : Google Scholar : PubMed/NCBI
13	Sioud M, Mobergslien A, Boudabous A and Fløisand Y: Evidence for the involvement of galectin-3 in mesenchymal stem cell suppression of allogeneic T-cell proliferation. Scand. J Immunol. 71:267–274. 2010.
14	Chen W, Huang Y, Han J, Yu L, Li Y, Lu Z, Li H, Liu Z, Shi C, Duan F and Xiao Y: Immunomodulatory effects of mesenchymal stromal cells-derived exosome. Immunol Res. 64:831–840. 2016. View Article : Google Scholar : PubMed/NCBI
15	Qu X, Liu X, Cheng K, Yang R and Zhao RC: Mesenchymal stem cells inhibit Th17 cell differentiation by IL-10 secretion. Exp Hematol. 40:761–770. 2012. View Article : Google Scholar : PubMed/NCBI
16	Xu G, Wang L, Chen W, Xue F, Bai X, Liang L, Shen X, Zhang M, Xia D and Liang T: Rapamycin and tacrolimus differentially modulate acute graft-versus-host disease in rats after liver transplantation. Liver Transpl. 16:357–363. 2010. View Article : Google Scholar : PubMed/NCBI
17	Hajkova M, Hermankova B, Javorkova E, Bohacova P, Zajicova A, Holan V and Krulova M: Mesenchymal stem cells attenuate the adverse effects of immunosuppressive drugs on distinct T cell subopulations. Stem Cell Rev Rep. 13:104–115. 2017. View Article : Google Scholar : PubMed/NCBI
18	Yang JX, Zhang N, Wang HW, Gao P, Yang QP and Wen QP: CXCR4 receptor overexpression in mesenchymal stem cells facilitates treatment of acute lung injury in rats. J Biol Chem. 290:1994–2006. 2015. View Article : Google Scholar : PubMed/NCBI
19	Tang RJ, Shen SN, Zhao XY, Nie YZ, Xu YJ, Ren J, Lv MM, Hou YY and Wang TT: Mesenchymal stem cells-regulated Treg cells suppress colitis-associated colorectal cancer. Stem Cell Res Ther. 6:712015. View Article : Google Scholar : PubMed/NCBI
20	Engela AU, Hoogduijn MJ, Boer K, Litjens NH, Betjes MG, Weimar W and Baan CC: Human adipose-tissue derived mesenchymal stem cells induce functional de-novo regulatory T cells with methylated FOXP3 gene DNA. Clin Exp Immunol. 173:343–354. 2013. View Article : Google Scholar : PubMed/NCBI
21	Laurence A, Tato CM, Davidson TS, Kanno Y, Chen Z, Yao Z, Blank RB, Meylan F, Siegel R, Hennighausen L, et al: Interleukin-2 signaling via STAT5 constrains T helper 17 cell generation. Immunity. 26:371–381. 2007. View Article : Google Scholar : PubMed/NCBI