Interferon-γ alters the immune-related miRNA expression of microvesicles derived from mesenchymal stem cells

Abstract

Increasing studies have demonstrated that interferon gamma (IFN-γ), which serves as a critical inflammatory cytokine, is essential to induce the immunosuppressive effects of mesenchymal stem cells (MSCs). However, the mechanisms underlying the enhanced immunosuppressive effects of IFN-γ-stimulated MSCs (γMSCs) are not fully understood. MSC-derived microvesicles (MSC-MVs) have been viewed as potential pivotal mediators of the immunosuppressive effects of MSCs. Moreover, microRNAs (miRNAs) are important regulators of immunological processes and can be shuttled from cell to cell by MVs. The aim of our study was to analyze the the miRNA expression signature of MVs derived from γMSCs (γMSC-MVs), which may provide better understanding of the immunosuppressive property of their parent cells. Through miRNA microarray and bioinformatics analysis, we found 62 significantly differentially expressed miRNAs (DEMs) in γMSC-MVs compared with MSC-MVs. And the potential target genes and signaling pathways regulated by DEMs were predicted and analyzed. Interestingly, many DEMs and predicted signaling pathways had been demonstrated to be involved in immunoregulation. Furthermore, the network between immunoregulation-related pathways and relevant DEMs was constructed. Collectively, our research on the miRNA repertoires of γMSC-MVs not only provides new perspectives into the mechanisms underlying the enhanced immunosuppressive property of γMSCs, but also paves the way to clinical application of these potent organelles in the future.

Keywords

mesenchymal stem cells / interferon gamma / microvesicles / microRNAs

References

[1] UccelliA, MorettaL, PistoiaV. Mesenchymal stem cells in health and disease. Nat Rev Immunol, 2008, 8(9): 726-736 PMID: 19172693

[2] ChanJL, TangKC, PatelAP, et al. . Antigen-presenting property of mesenchymal stem cells occurs during a narrow window at low levels of interferon-gamma. Blood, 2006, 107(12): 4817-4824 PMID: 16493000 PMCID: 1895812

[3] KramperaM, CosmiL, AngeliR, et al. . Role for interferon-gamma in the immunomodulatory activity of human bone marrow mesenchymal stem cells. Stem Cells, 2006, 24(2): 386-398 PMID: 16123384

[4] ShengH, WangY, JinY, et al. . A critical role of IFNgamma in priming MSC-mediated suppression of T cell proliferation through up-regulation of B7-H1. Cell Res, 2008, 18(8): 846-857 PMID: 18607390

[5] TkachM, TheryC. Communication by extracellular vesicles: where we are and where we need to go. Cell, 2016, 164(6): 1226-1232 PMID: 26967288

[6] FierabracciA, DelF A, LucianoR, et al. . Recent advances in mesenchymal stem cell immunomodulation: the role of microvesicles. Cell Transplant, 2015, 24(2): 133-149 PMID: 24268069

[7] BudoniM, FierabracciA, LucianoR, et al. . The immunosuppressive effect of mesenchymal stromal cells on B lymphocytes is mediated by membrane vesicles. Cell Transplant, 2013, 22(2): 369-379 PMID: 23433427

[8] MokarizadehA, DelirezhN, MorshediA, et al. . Microvesicles derived from mesenchymal stem cells: potent organelles for induction of tolerogenic signaling. Immunol Lett, 2012, 147(1-2): 47-54 PMID: 22705267

[9] AkyurekliC, LeY, RichardsonRB, et al. . A systematic review of preclinical studies on the therapeutic potential of mesenchymal stromal cell-derived microvesicles. Stem Cell Rev, 2015, 11(1): 150-160 PMID: 25091427

[10] XiaoC, RajewskyK. MicroRNA control in the immune system: basic principles. Cell, 2009, 136(1): 26-36 PMID: 19135886

[11] CollinoF, DeregibusMC, BrunoS, et al. . Microvesicles derived from adult human bone marrow and tissue specific mesenchymal stem cells shuttle selected pattern of miRNAs. PLoS One, 2010, 5(7): e11803 PMID: 20668554 PMCID: 2910725

[12] UedaR, KohanbashG, SasakiK, et al. . Dicer-regulated microRNAs 222 and 339 promote resistance of cancer cells to cytotoxic T-lymphocytes by down-regulation of ICAM-1. Proc Natl Acad Sci USA, 2009, 106(26): 10746-10751 PMID: 19520829 PMCID: 2705554

[13] RaoR, NagarkattiP, NagarkattiM. Role of miRNA in the regulation of inflammatory genes in staphylococcal enterotoxin B-induced acute inflammatory lung injury and mortality. Toxicol Sci, 2015, 144(2): 284-297 PMID: 25564423 PMCID: 4372662

[14] YinY, CaiX, ChenX, et al. . Tumor-secreted miR-214 induces regulatory T cells: a major link between immune evasion and tumor growth. Cell Res, 2014, 24(10): 1164-1180 PMID: 25223704 PMCID: 4185347

[15] TsukermanP, EnkJ, MandelboimO. Metastamir-mediated immune evasion: miR-10b downregulates the stress-induced molecule MICB, hence avoid recognition by NKG2D receptor. Oncoimmunology, 2013, 2(1): e22245 PMID: 23479551 PMCID: 3583910

[16] KoukosG, PolytarchouC, KaplanJL, et al. . A microRNA signature in pediatric ulcerative colitis: deregulation of the miR-4284/CXCL5 pathway in the intestinal epithelium. Inflamm Bowel Dis, 2015, 21(5): 996-1005 PMID: 25738378 PMCID: 4402238

[17] ChoKJ, SongJ, OhY, et al. . MicroRNA-Let-7a regulates the function of microglia in inflammation. Mol Cell Neurosci, 2015, 68: 167-176 PMID: 26221772

[18] LiuY, WangX, JiangJ, et al. . Modulation of T cell cytokine production by miR-144* with elevated expression in patients with pulmonary tuberculosis. Mol Immunol, 2011, 48(9-10): 1084-1090 PMID: 21367459

[19] HuangB, ZhaoJ, LeiZ, et al. . miR-142-3p restricts cAMP production in CD4+CD25-T cells and CD4+CD25+ TREG cells by targeting AC9 mRNA. EMBO Rep, 2009, 10(2): 180-185 PMID: 19098714

[20] DingS, LiangY, ZhaoM, et al. . Decreased microRNA-142-3p/5p expression causes CD4+ T cell activation and B cell hyperstimulation in systemic lupus erythematosus. Arthritis Rheum, 2012, 64(9): 2953-2963 PMID: 22549634

[21] ZhuQY, LiuQ, ChenJX, et al. . MicroRNA-101 targets MAPK phosphatase-1 to regulate the activation of MAPKs in macrophages. J Immunol, 2010, 185(12): 7435-7442 PMID: 21068409

[22] ChenZ, GibsonTB, RobinsonF, et al. . MAP kinases. Chem Rev, 2001, 101(8): 2449-2476 PMID: 11749383

[23] LiuY, ZhangR, YanK, et al. . Mesenchymal stem cells inhibit lipopolysaccharide-induced inflammatory responses of BV2 microglial cells through TSG-6. J Neuroinflammation., 2014, 11: 135 PMID: 25088370 PMCID: 4128538

[24] ZhuH, YangF, TangB, et al. . Mesenchymal stem cells attenuated PLGA-induced inflammatory responses by inhibiting host DC maturation and function. Biomaterials, 2015, 53: 688-698 PMID: 25890764

[25] HofbauerR, KayeAD, KapiotisS, et al. . The immune system and the effects of non-volatile anesthetics on neutrophil transmigration through endothelial cell monolayers. Curr Pharm Des, 1999, 5(12): 1015-1027 PMID: 10607859

[26] GuoZ, KongQ, LiuC, et al. . DCAF1 controls T-cell function via p53-dependent and -independent mechanisms. Nat Commun, 2016, 7: 10307 PMID: 26728942

[27] MaillardI, AdlerSH, PearWS. Notch and the immune system. Immunity, 2003, 19(6): 781-791 PMID: 14670296

[28] ShiD, LiaoL, ZhangB, et al. . Human adipose tissue-derived mesenchymal stem cells facilitate the immunosuppressive effect of cyclosporin A on T lymphocytes through Jagged-1-mediated inhibition of NF-kappaB signaling. Exp Hematol, 2011, 39(2): 214-224 PMID: 21078360