Mechanisms of the immunosuppressive effects of mouse adipose tissue-derived mesenchymal stromal cells on mouse alloreactively stimulated spleen cells

Nagaya,Ryo; Mizuno-Kamiya,Masako; Takayama,Eiji; Kawaki,Harumi; Onoe,Ippei; Tanabe,Toshiichiro; Nagahara,Kuniteru; Kondoh,Nobuo

doi:10.3892/etm.2013.1382

Mechanisms of the immunosuppressive effects of mouse adipose tissue-derived mesenchymal stromal cells on mouse alloreactively stimulated spleen cells

Authors:
- Ryo Nagaya
- Masako Mizuno-Kamiya
- Eiji Takayama
- Harumi Kawaki
- Ippei Onoe
- Toshiichiro Tanabe
- Kuniteru Nagahara
- Nobuo Kondoh
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Affiliations: Department of Oral Implantology, Asahi University School of Dentistry, Mizuho-shi, Gifu 501-0296, Japan, Department of Oral Biochemistry, Asahi University School of Dentistry, Mizuho-shi, Gifu 501-0296, Japan
Published online on: November 6, 2013 https://doi.org/10.3892/etm.2013.1382
Pages: 17-22

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Abstract

The mechanisms of immunomodulation by mesenchymal stromal cells remain poorly understood. In this study, the effects of mouse adipose tissue‑derived mesenchymal stromal cells (ASCs) on mouse spleen cells alloreactively stimulated by anti-CD3 and anti‑CD28 antibody‑coated (anti-CD3/CD28) beads were observed. Production of interferon-γ by the anti-CD3/CD28 bead-stimulated spleen cells was significantly suppressed in co-culture with ASCs. However, an augmented intensity of CD69 on the stimulated spleen cells was not suppressed in the presence of ASCs. The immunosuppressive effects of ASCs were partially mediated by one or more soluble factors (26% suppression). However, the ASCs require cell-cell contact in order to maximally exert suppression (88%). The suppressive effect of ASCs mediated by direct cell contact was partially reversed following knockdown of β2 microglobulin, a component of the major histocompatibility complex (MHC) class I molecule, with siRNA. The results of the study demonstrated that ASCs have significant immune modulatory effects on alloreactively stimulated spleen cells. The effects of ASCs on spleen cells are dependent on soluble factor(s) and cell contact, which is mediated by the MHC class I complex on ASCs.

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1	Friedenstein AJ, Gorskaja JF and Kulagina NN: Fibroblast precursors in normal and irradiated mouse hematopoietic organs. Exp Hematol. 4:267–274. 1976.PubMed/NCBI
2	Prockop DJ: Marrow stromal cells as stem cells for nonhematopoietic tissues. Science. 276:71–74. 1997. View Article : Google Scholar : PubMed/NCBI
3	Zuk PA, Zhu M, Mizuno H, Huang J, Futrell JW, Katz AJ, Benhaim P, Lorenz HP and Hedrick MH: Multilineage cells from human adipose tissue: implications for cell-based therapies. Tissue Eng. 7:211–228. 2001. View Article : Google Scholar : PubMed/NCBI
4	In ‘t Anker PS, Scherjon SA, Kleijburg-van der Keur C, de Groot-Swings GM, Claas FH, Fibbe WE and Kanhai HH: Isolation of mesenchymal stem cells of fetal or maternal origin from human placenta. Stem Cells. 22:1338–1345. 2004.
5	In ‘t Anker PS, Scherjon SA, Kleijburg-van der Keur C, Noort WA, Claas FH, Willemze R, Fibbe WE and Kanhai HH: Amniotic fluid as a novel source of mesenchymal stem cells for therapeutic transplantation. Blood. 102:1548–1549. 2003.PubMed/NCBI
6	In ‘t Anker PS, Noort WA, Scherjon SA, Kleijburg-van der Keur C, Kruisselbrink AB, van Bezooijen RL, Beekhuizen W, Willemze R, Kanhai HH and Fibbe WE: Mesenchymal stem cells in human second-trimester bone marrow, liver, lung, and spleen exhibit a similar immunophenotype but a heterogeneous multilineage differentiation potential. Haematologica. 88:845–852. 2003.
7	Fraser JK, Schreiber R, Strem B, Zhu M, Alfonso Z, Wulur I and Hedrick MH: Plasticity of human adipose stem cells toward endothelial cells and cardiomyocytes. Nat Clin Pract Cardiovasc Med. 3(Suppl 1): S33–S37. 2006. View Article : Google Scholar : PubMed/NCBI
8	Le Blanc K, Tammik L, Sundberg B, Haynesworth SE and Ringdén O: Mesenchymal stem cells inhibit and stimulate mixed lymphocyte cultures and mitogenic responses independently of the major histocompatibility complex. Scand J Immunol. 57:11–20. 2003.PubMed/NCBI
9	Potian JA, Aviv H, Ponzio NM, Harrison JS and Rameshwar P: Veto-like activity of mesenchymal stem cells: functional discrimination between cellular responses to alloantigens and recall antigens. J Immunol. 171:3426–3434. 2003. View Article : Google Scholar : PubMed/NCBI
10	Tse WT, Pendleton JD, Beyer WM, Egalka MC and Guinan EC: Suppression of allogeneic T-cell proliferation by human marrow stromal cells: implications in transplantation. Transplantation. 75:389–397. 2003. View Article : Google Scholar : PubMed/NCBI
11	Di Nicola M, Carlo-Stella C, Magni M, Milanesi M, Longoni PD, Matteucci P, Grisanti S and Gianni AM: Human bone marrow stromal cells suppress T- lymphocyte proliferation induced by cellular or nonspecific mitogenic stimuli. Blood. 99:3838–3843. 2002.
12	Plumas J, Chaperot L, Richard MJ, Molens JP, Bensa JC and Favrot MC: Mesenchymal stem cells induce apoptosis of activated T cells. Leukemia. 19:1597–1604. 2005. View Article : Google Scholar : PubMed/NCBI
13	Djouad F, Plence P, Bony C, Tropel P, Apparailly F, Sany J, Noël D and Jorgensen C: Immunosuppressive effect of mesenchymal stem cells favors tumor growth in allogeneic animals. Blood. 102:3837–3844. 2003. View Article : Google Scholar : PubMed/NCBI
14	Corcione A, Benvenuto F, Ferretti E, Giunti D, Cappiello V, Cazzanti F, Risso M, Gualandi F, Mancardi GL, Pistoia V and Uccelli A: Human mesenchymal stem cells modulate B-cell functions. Blood. 107:367–372. 2006. View Article : Google Scholar : PubMed/NCBI
15	Spaggiari GM, Capobianco A, Abdelrazik H, Becchetti F, Mingari MC and Moretta L: Mesenchymal stem cells inhibit natural killer-cell proliferation, cytotoxicity, and cytokine production: role of indoleamine 2,3-dioxygenase and prostaglandin E2. Blood. 111:1327–1333. 2008. View Article : Google Scholar : PubMed/NCBI
16	English K, Ryan JM, Tobin L, Murphy MJ, Barry FP and Mahon BP: Cell contact, prostaglandin E(2) and transforming growth factor beta 1 play non-redundant roles in human mesenchymal stem cell induction of CD4⁺CD25^High forkhead box P3⁺ regulatory T cells. Clin Exp Immunol. 156:149–160. 2009. View Article : Google Scholar : PubMed/NCBI
17	Le Blanc K, Rasmusson I, Sundberg B, Götherström C, Hassan M, Uzunel M and Ringdén O: Treatment of severe acute graft-versus-host disease with third party haploidentical mesenchymal stem cells. Lancet. 363:1439–1441. 2004.PubMed/NCBI
18	Hoogduijn MJ, Popp FC, Grohnert A, Crop MJ, van Rhijn M, Rowshani AT, Eggenhofer E, Renner P, Reinders ME, Rabelink TJ, van der Laan LJ, Dor FJ, Ijzermans JN, Genever PG, Lange C, Durrbach A, Houtgraaf JH, Christ B, Seifert M, Shagidulin M, Donckier V, Deans R, Ringden O, Perico N, Remuzzi G, Bartholomew A, Schlitt HJ, Weimar W, Baan CC and Dahlke MH; MISOT Study Group. Advancement of mesenchymal stem cell therapy in solid organ transplantation (MISOT). Transplantation. 90:124–126. 2010. View Article : Google Scholar : PubMed/NCBI
19	Le Blanc K, Frassoni F, Ball L, Locatelli F, Roelofs H, Lewis I, Lanino E, Sundberg B, Bernardo ME, Remberger M, Dini G, Egeler RM, Bacigalupo A and Fibbe W; Ringdén O; Development Committee of the Eurpoean Group for Blood and Marrow Transplantation. Mesenchymal stem cells for treatment of steroid-resistant, severe, acute graft-versus-host disease: a phase II study. Lancet. 371:1579–1586. 2008.
20	Ciccocioppo R, Bernardo ME, Sgarella A, Maccario R, Avanzini MA, Ubezio C, Minelli A, Alvisi C, Vanoli A, Calliada F, Dionigi P, Perotti C, Locatelli F and Corazza GR: Autologous bone marrow-derived mesenchymal stromal cells in the treatment of fistulising Crohn’s disease. Gut. 60:788–798. 2011.PubMed/NCBI
21	Tse WT, Pendleton JD, Beyer WM, Egalka MC and Guinan EC: Suppression of allogeneic T-cell proliferation by human marrow stromal cells: implications in transplantation. Transplantation. 75:389–397. 2003. View Article : Google Scholar : PubMed/NCBI
22	Melief SM, Zwaginga JJ, Fibbe WE and Roelofs H: Adipose tissue-derived multipotent stromal cells have a higher immunomodulatory capacity than their bone marrow-derived counterparts. Stem Cells Transl Med. 2:455–463. 2013. View Article : Google Scholar
23	Pittenger MF, Mackay AM, Beck SC, Jaiswal RK, Douglas R, Mosca JD, Moorman MA, Simonetti DW, Craig S and Marshak DR: Multilineage potential of adult human mesenchymal stem cells. Science. 284:143–147. 1999. View Article : Google Scholar : PubMed/NCBI
24	Kondoh N, Ishikawa T, Ohkura S, Arai M, Hada A, Yamazaki Y, Kitagawa Y, Shindoh M, Takahashi M, Ando T, Sato Y, Izumo T, Hitomi K and Yamamoto M: Gene expression signatures that classify the mode of invasion of primary oral squamous cell carcinomas. Mol Carcinog. 47:744–756. 2008. View Article : Google Scholar : PubMed/NCBI
25	Lim JY, Park MJ, Im KI, Kim N, Jeon EJ, Kim EJ, Cho ML and Cho SG: Combination cell therapy using mesenchymal stem cells and regulatory T cells provides a synergistic immunomodulatory effect associated with reciprocal regulation of Th1/Th2 and Th17/Treg cells in a murine acute graft-versus-host disease model. Cell Transplant. Feb 26–2013.(Epub ahead of print).
26	Schroder K, Hertzog PJ, Ravasi T and Hume DA: Interferon-gamma: an overview of signals, mechanisms and functions. J Leukoc Biol. 75:163–189. 2004. View Article : Google Scholar : PubMed/NCBI
27	Cambiaggi C, Scupoli MT, Cestari T, Gerosa F, Carra G, Tridente G and Accolla RS: Constitutive expression of CD69 in interspecies T-cell hybrids and locus assignment to human chromosome 12. Immunogenetics. 36:117–120. 1992. View Article : Google Scholar : PubMed/NCBI
28	Yang HM, Sung JH, Choi YS, Lee HJ, Roh CR, Kim J, Shin M, Song S, Kwon CH, Joh JW and Kim SJ: Enhancement of the immunosuppressive effect of human adipose tissue-derived mesenchymal stromal cells through HLA-G1 expression. Cytotherapy. 14:70–79. 2012. View Article : Google Scholar : PubMed/NCBI
29	Nasef A, Mathieu N, Chapel A, Frick J, François S, Mazurier C, Boutarfa A, Bouchet S, Gorin NC, Thierry D and Fouillard L: Immunosuppressive effects of mesenchymal stem cells: involvement of HLA-G. Transplantation. 84:231–237. 2007. View Article : Google Scholar : PubMed/NCBI
30	Alberts B, Johnson A, Lewis J, Raff M, Roberts K and Walter P: T cells and MHC proteins. Molecular biology of the cell. 5th edition. Garland Science; New York, NY: pp. 1569–1588. 2008
31	Sato K, Ozaki K, Oh I, Meguro A, Hatanaka K, Nagai T, Muroi K and Ozawa K: Nitric oxide plays a critical role in suppression of T-cell proliferation by mesenchymal stem cells. Blood. 109:228–234. 2007. View Article : Google Scholar : PubMed/NCBI
32	Yang HM, Sung JH, Choi YS, Lee HJ, Roh CR, Kim J, Shin M, Song S, Kwon CH, Joh JW and Kim SJ: Enhancement of the immunosuppressive effect of human adipose tissue-derived mesenchymal stromal cells through HLA-G1 expression. Cytotherapy. 14:70–79. 2012. View Article : Google Scholar : PubMed/NCBI
33	Musso A, Zocchi MR and Poggi A: Relevance of the mevalonate biosynthetic pathway in the regulation of bone marrow mesenchymal stromal cell-mediated effects on T-cell proliferation and B-cell survival. Haematologica. 96:16–23. 2011. View Article : Google Scholar : PubMed/NCBI