Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

MicroRNA-663 induces immune dysregulation by inhibiting TGF-β1 production in bone marrow-derived mesenchymal stem cells in patients with systemic lupus erythematosus

Cellular & Molecular Immunology volume 16, pages 260–274 (2019)Cite this article

Abstract

Mesenchymal stem cells (MSCs) are critical for immune regulation. Although several microRNAs (miRNAs) have been shown to participate in autoimmune pathogenesis by affecting lymphocyte development and function, the roles of miRNAs in MSC dysfunction in autoimmune diseases remain unclear. Here, we show that patients with systemic lupus erythematosus (SLE) display a unique miRNA signature in bone marrow-derived MSCs (BMSCs) compared with normal controls, among which miR-663 is closely associated with SLE disease activity. MiR-663 inhibits the proliferation and migration of BMSCs and impairs BMSC-mediated downregulation of follicular T helper (Tfh) cells and upregulation of regulatory T (Treg) cells by targeting transforming growth factor β1 (TGF-β1). MiR-663 overexpression weakens the therapeutic effect of BMSCs, while miR-663 inhibition improves the remission of lupus disease in MRL/lpr mice. Thus, miR-663 is a key mediator of SLE BMSC regulation and may serve as a new therapeutic target for the treatment of lupus.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6

Similar content being viewed by others

References

  1. Cho KA, Lee JK, Kim YH, Park M, Woo SY, Ryu KH. Mesenchymal stem cells ameliorate b-cell-mediated immune responses and increase il-10-expressing regulatory b cells in an ebi3-dependent manner. Cell Mol Immunol 2017 e-pub ahead of print 2 Jan 2017; doi:https://doi.org/10.1038/cmi.2016.59

    Article  CAS  Google Scholar 

  2. Zhao LD, Liang D, Wu XN, Li Y, Niu JW, Zhou C et al. Contribution and underlying mechanisms of cxcr4 overexpression in patients with systemic lupus erythematosus. Cell Mol Immunol 2017; 14: 842–849.

    Article  CAS  PubMed  Google Scholar 

  3. Sun LY, Zhang HY, Feng XB, Hou YY, Lu LW, Fan LM. Abnormality of bone marrow-derived mesenchymal stem cells in patients with systemic lupus erythematosus. Lupus 2007; 16: 121–128.

    Article  CAS  PubMed  Google Scholar 

  4. Li X, Liu L, Meng D, Wang D, Zhang J, Shi D et al. Enhanced apoptosis and senescence of bone-marrow-derived mesenchymal stem cells in patients with systemic lupus erythematosus. Stem Cells Dev 2012; 21: 2387–2394.

    Article  CAS  PubMed  Google Scholar 

  5. Ma X, Che N, Gu Z, Huang J, Wang D, Liang J et al. Allogenic mesenchymal stem cell transplantation ameliorates nephritis in lupus mice via inhibition of b-cell activation. Cell Transplant 2013; 22: 2279–2290.

    Article  PubMed  Google Scholar 

  6. Shi D, Li X, Chen H, Che N, Zhou S, Lu Z et al. High level of reactive oxygen species impaired mesenchymal stem cell migration via overpolymerization of f-actin cytoskeleton in systemic lupus erythematosus. Pathol Biol 2014; 62: 382–390.

    Article  CAS  PubMed  Google Scholar 

  7. Wang D, Feng X, Lu L, Konkel JE, Zhang H, Chen Z et al. A cd8 T cell/indoleamine 2,3-dioxygenase axis is required for mesenchymal stem cell suppression of human systemic lupus erythematosus. Arthritis Rheumatol 2014; 66: 2234–2245.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Gu F, Molano I, Ruiz P, Sun L, Gilkeson GS. Differential effect of allogeneic versus syngeneic mesenchymal stem cell transplantation in mrl/lpr and (nzb/nzw)f1 mice. Clin Immunol 2012; 145: 142–152.

    Article  CAS  PubMed  Google Scholar 

  9. Wang D, Li J, Zhang Y, Zhang M, Chen J, Li X et al. Umbilical cord mesenchymal stem cell transplantation in active and refractory systemic lupus erythematosus: a multicenter clinical study. Arthritis Res Ther 2014; 16: R79.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Zhou K, Zhang H, Jin O, Feng X, Yao G, Hou Y et al. Transplantation of human bone marrow mesenchymal stem cell ameliorates the autoimmune pathogenesis in mrl/lpr mice. Cell Mol Immunol 2008; 5: 417–424.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Sun L, Akiyama K, Zhang H, Yamaza T, Hou Y, Zhao S et al. Mesenchymal stem cell transplantation reverses multiorgan dysfunction in systemic lupus erythematosus mice and humans. Stem Cells 2009; 27: 1421–1432.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Sun L, Wang D, Liang J, Zhang H, Feng X, Wang H et al. Umbilical cord mesenchymal stem cell transplantation in severe and refractory systemic lupus erythematosus. Arthritis Rheum 2010; 62: 2467–2475.

    Article  CAS  PubMed  Google Scholar 

  13. Tang Y, Luo X, Cui H, Ni X, Yuan M, Guo Y et al. Microrna-146a contributes to abnormal activation of the type I interferon pathway in human lupus by targeting the key signaling proteins. Arthritis Rheum 2009; 60: 1065–1075.

    Article  CAS  PubMed  Google Scholar 

  14. Carlsen AL, Schetter AJ, Nielsen CT, Lood C, Knudsen S, Voss A et al. Circulating microrna expression profiles associated with systemic lupus erythematosus. Arthritis Rheum 2013; 65: 1324–1334.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Dai Y, Sui W, Lan H, Yan Q, Huang H, Huang Y. Comprehensive analysis of microrna expression patterns in renal biopsies of lupus nephritis patients. Rheumatol Int 2009; 29: 749–754.

    Article  CAS  PubMed  Google Scholar 

  16. Shen N, Liang D, Tang Y, de Vries N, Tak PP. Micrornas—novel regulators of systemic lupus erythematosus pathogenesis. Nat Rev Rheumatol 2012; 8: 701–709.

    Article  CAS  PubMed  Google Scholar 

  17. Zhao S, Wang Y, Liang Y, Zhao M, Long H, Ding S et al. Microrna-126 regulates DNA methylation in CD4+ T cells and contributes to systemic lupus erythematosus by targeting DNA methyltransferase 1. Arthritis Rheum 2011; 63: 1376–1386.

    Article  CAS  PubMed  Google Scholar 

  18. Clark EA, Kalomoiris S, Nolta JA, Fierro FA. Concise review: microrna function in multipotent mesenchymal stromal cells. Stem Cells 2014; 32: 1074–1082.

    Article  CAS  PubMed  Google Scholar 

  19. Ueno H, Banchereau J, Vinuesa CG. Pathophysiology of T follicular helper cells in humans and mice. Nat Immunol 2015; 16: 142–152.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Choi SC, Hutchinson TE, Titov AA, Seay HR, Li S, Brusko TM et al. The lupus susceptibility gene PBX1 regulates the balance between follicular helper T cell and regulatory T cell differentiation. J Immunol 2016; 197: 458–469.

    Article  CAS  PubMed  Google Scholar 

  21. Trucci VM, Salum FG, Figueiredo MA, Cherubini K. Interrelationship of dendritic cells, type 1 interferon system, regulatory t cells and toll-like receptors and their role in lichen planus and lupus erythematosus — a literature review. Arch Oral Biol 2013; 58: 1532–1540.

    Article  CAS  PubMed  Google Scholar 

  22. Xiao F, Lin X, Tian J, Wang X, Chen Q, Rui K et al. Proteasome inhibition suppresses th17 cell generation and ameliorates autoimmune development in experimental sjogren's syndrome. Cell Mol Immunol 2017 e-pub ahead of print 10 Jul 2017; doi: https://doi.org/10.1038/cmi.2017.8.

    Article  CAS  Google Scholar 

  23. Tili E, Michaille JJ, Adair B, Alder H, Limagne E, Taccioli C et al. Resveratrol decreases the levels of mir-155 by upregulating mir-663, a microrna targeting junb and jund. Carcinogenesis 2010; 31: 1561–1566.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Takahashi H, Kanno T, Nakayamada S, Hirahara K, Sciume G, Muljo SA et al. Tgf-beta and retinoic acid induce the microrna mir-10a, which targets bcl-6 and constrains the plasticity of helper t cells. Nat Immunol 2012; 13: 587–595.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Tang Y, Wu X, Lei W, Pang L, Wan C, Shi Z et al. TGF-beta1-induced migration of bone mesenchymal stem cells couples bone resorption with formation. Nat Med 2009; 15: 757–765.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Zhao W, Wang C, Liu R, Wei C, Duan J, Liu K et al. Effect of TGF-beta1 on the migration and recruitment of mesenchymal stem cells after vascular balloon injury: Involvement of matrix metalloproteinase-14. Sci Rep 2016; 6: 21176.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Liu R, Li X, Zhang Z, Zhou M, Sun Y, Su D et al. Allogeneic mesenchymal stem cells inhibited t follicular helper cell generation in rheumatoid arthritis. Sci Rep 2015; 5: 12777.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Reisch N, Engler A, Aeschlimann A, Simmen BR, Michel BA, Gay RE et al. Dream is reduced in synovial fibroblasts of patients with chronic arthritic pain: Is it a suitable target for peripheral pain management? Arthritis Res Ther 2008; 10: R60.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  29. Le Blanc K, Mougiakakos D. Multipotent mesenchymal stromal cells and the innate immune system. Nat Rev Immunol 2012; 12: 383–396.

    Article  CAS  PubMed  Google Scholar 

  30. Peng S, Gao D, Gao C, Wei P, Niu M, Shuai C. Micrornas regulate signaling pathways in osteogenic differentiation of mesenchymal stem cells (review). Mol Med Rep 2016; 14: 623–629.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Prabahar A, Natarajan J. Microrna mediated network motifs in autoimmune diseases and its crosstalk between genes, functions and pathways. J Immunol Methods 2017; 440: 19–26.

    Article  CAS  PubMed  Google Scholar 

  32. Pauley KM, Cha S, Chan EK. Microrna in autoimmunity and autoimmune diseases. J Autoimmun 2009; 32: 189–194.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Zhou H, Huang X, Cui H, Luo X, Tang Y, Chen S et al. Mir-155 and its star-form partner mir-155* cooperatively regulate type i interferon production by human plasmacytoid dendritic cells. Blood 2010; 116: 5885–5894.

    Article  CAS  PubMed  Google Scholar 

  34. Jian P, Li ZW, Fang TY, Jian W, Zhuan Z, Mei LX et al. Retinoic acid induces hl-60 cell differentiation via the upregulation of mir-663. J Hematol Oncol 2011; 4: 20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Li Q, Cheng Q, Chen Z, Peng R, Chen R, Ma Z et al. Microrna-663 inhibits the proliferation, migration and invasion of glioblastoma cells via targeting tgf-beta1. Oncol Rep 2016; 35: 1125–1134.

    Article  CAS  PubMed  Google Scholar 

  36. Carden T, Singh B, Mooga V, Bajpai P, Singh KK. Epigenetic modification of mir-663 controls mitochondria-to-nucleus retrograde signaling and tumor progression. J Biol Chem 2017; 292: 20694–20706 e-pub ahead of print 24 Oct 2017; doi: https://doi.org/10.1074/jbc.M117.797001.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Afonyushkin T, Oskolkova OV, Bochkov VN. Permissive role of mir-663 in induction of vegf and activation of the atf4 branch of unfolded protein response in endothelial cells by oxidized phospholipids. Atherosclerosis 2012; 225: 50–55.

    Article  CAS  PubMed  Google Scholar 

  38. Li P, Zhu N, Yi B, Wang N, Chen M, You X et al. Microrna-663 regulates human vascular smooth muscle cell phenotypic switch and vascular neointimal formation. Circ Res 2013; 113: 1117–1127.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Liu ZY, Zhang GL, Wang MM, Xiong YN, Cui HQ. Microrna-663 targets tgfb1 and regulates lung cancer proliferation. Asian Pac J Cancer Prev 2011; 12: 2819–2823.

    PubMed  Google Scholar 

  40. Hu H, Li S, Cui X, Lv X, Jiao Y, Yu F et al. The overexpression of hypomethylated mir-663 induces chemotherapy resistance in human breast cancer cells by targeting heparin sulfate proteoglycan 2 (hspg2). J Biol Chem 2013; 288: 10973–10985.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Oshimori N, Fuchs E. The harmonies played by tgf-beta in stem cell biology. Cell Stem Cell 2012; 11: 751–764.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Chen W, Jin W, Hardegen N, Lei KJ, Li L, Marinos N et al. Conversion of peripheral cd4+cd25- naive t cells to cd4+cd25+ regulatory t cells by tgf-beta induction of transcription factor foxp3. J Exp Med 2003; 198: 1875–1886.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Linterman MA, Pierson W, Lee SK, Kallies A, Kawamoto S, Rayner TF et al. Foxp3+ follicular regulatory t cells control the germinal center response. Nat Med 2011; 17: 975–982.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Chung Y, Tanaka S, Chu F, Nurieva RI, Martinez GJ, Rawal S et al. Follicular regulatory t cells expressing foxp3 and bcl-6 suppress germinal center reactions. Nat Med 2011; 17: 983–988.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Vaeth M, Muller G, Stauss D, Dietz L, Klein-Hessling S, Serfling E et al. Follicular regulatory t cells control humoral autoimmunity via nfat2-regulated cxcr5 expression. J Exp Med 2014; 211: 545–561.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Hochberg MC. Updating the american college of rheumatology revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 1997; 40: 1725.

    Article  CAS  PubMed  Google Scholar 

  47. Kikawada E, Lenda DM, Kelley VR. Il-12 deficiency in mrl-fas(lpr) mice delays nephritis and intrarenal ifn-gamma expression, and diminishes systemic pathology. J Immunol 2003; 170: 3915–3925.

    Article  CAS  PubMed  Google Scholar 

Download references

The work was supported by the Major International (Regional) Joint Research Project (No.81720108020), National Natural Science Foundation of China (No. 81373199, 81501347 and 81370730, 81273304), National Natural Science Foundation of Jiangsu (BK20150098), and Jiangsu Province Major Research and Development Program (BE2015602) and Jiangsu Province 333 Talant Grant (BRA2016001). WC was supported by the Intramural Research Program of NIH, NIDCR.

Author information

Author notes

  1. These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Rheumatology and Immunology, The Affiliated Drum Tower Hospital of Nanjing University Medical School, 210008, Nanjing, China

    Linyu Geng, Xiaojun Tang, Kangxing Zhou, Dandan Wang, Shiying Wang, Genhong Yao, Weiwei Chen, Xuebing Feng & Lingyun Sun

  2. Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing University, 210000, Nanjing, China

    Xiang Gao

  3. Mucosal Immunology Section, OPCB, National Institute of Dental and Craniofacial Research, National Institutes of Health, 20892-2190, Bethesda, MD, USA

    Wanjun Chen

  4. Department of Anatomy and Cell Biology, School of Dental Medicine, University of Pennsylvania, 19104-6004, Philadelphia, PA, USA

    Songtao Shi

  5. Joint Molecular Rheumatology Laboratory of the Institute of Health Sciences and Shanghai Renji Hospital, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, and Shanghai Jiaotong University School of Medicine, Shanghai, China

    Nan Shen

Authors
  1. Linyu Geng
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Xiaojun Tang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Kangxing Zhou
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Dandan Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Shiying Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Genhong Yao
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Weiwei Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Xiang Gao
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Wanjun Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Songtao Shi
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Nan Shen
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Xuebing Feng
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Lingyun Sun
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

LS designed, coordinated and supervised the study. LG carried out most of the experiments, performed the data acquisition and analysis, and wrote the manuscript. XF contributed to the data interpretation and manuscript drafting. KZ, XG, WC, SS and NS participated in the study design. SW, GY, XT, WC and DW participated in human sample collection and breeding of MRL/lpr mice. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Xuebing Feng or Lingyun Sun.

Ethics declarations

Conflict of interest

The authors declare no conflict of interest.

Electronic supplementary material

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Geng, L., Tang, X., Zhou, K. et al. MicroRNA-663 induces immune dysregulation by inhibiting TGF-β1 production in bone marrow-derived mesenchymal stem cells in patients with systemic lupus erythematosus. Cell Mol Immunol 16, 260–274 (2019). https://doi.org/10.1038/cmi.2018.1

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/cmi.2018.1

This article is cited by

Search

Advanced search

Quick links