Are We Right to Consider Mesenchymal Stem Cells to Be a New Perspective for Patients with Juvenile Idiopathic Arthritis?

  • Krzysztof Orczyk
  • Elzbieta Smolewska


Juvenile idiopathic arthritis (JIA) is the most common cause of chronic arthritis in childhood. Up to 50% of patients are resistant to standard therapy, which includes non-steroid anti-inflammatory drugs, corticosteroids, disease-modifying anti-rheumatic drugs and biologic therapies. Intra-articular injection of mesenchymal stem cells (MSCs) is proposed as a new approach to JIA treatment. MSCs can modulate inflammation via mechanisms of both adaptive and innate immune response. They are able to inhibit T and B cell proliferation, promote regulatory T cells, suppress the maturation of dendritic cells, stimulate macrophage differentiation into M2 phenotype and reduce effectiveness of natural killer cells. They also secrete plethora of soluble factors which influence joint inflammation. Recent clinical studies reviewed in the article provide promising results which may suggest including intra-articular injection of MSCs in therapy of patients with oligoarticular JIA.


Mesenchymal stem cells Juvenile idiopathic arthritis Pathogenesis 



This work was partially supported by the grant No. 503/8-000-04/503-81-002 from Medical University of Lodz, Poland.

Compliance with Ethical Standards

Conflict of interest

Authors declare no conflict of interests.


  1. Abdelrazik H, Spaggiari GM, Chiossone L et al (2011) Mesenchymal stem cells expanded in human platelet lysate display a decreased inhibitory capacity on T- and NK-cell proliferation and function. Eur J Immunol 41:3281–3290CrossRefPubMedGoogle Scholar
  2. Ansboro S, Roelofs AJ, De Bari C (2017) Mesenchymal stem cells for the management of rheumatoid arthritis: immune modulation, repair or both? Curr Opin Rheumatol 29:201–207CrossRefPubMedGoogle Scholar
  3. Bartholomew A, Sturgeon C, Siatskas M et al (2002) Mesenchymal stem cells suppress lymphocyte proliferation in vitro and prolong skin graft survival in vivo. Exp Hematol 30:42–48CrossRefPubMedGoogle Scholar
  4. Bocelli-Tyndall C, Bracci L, Spagnoli G et al (2007) Bone marrow mesenchymal stromal cells (BM-MSCs) from healthy donors and auto-immune disease patients reduce the proliferation of autologous- and allogeneic-stimulated lymphocytes in vitro. Rheumatology 46:403–408CrossRefPubMedGoogle Scholar
  5. Burt RK, Slavin S, Burns WH, Marmont AM (2002) Induction of tolerance in autoimmune diseases by hematopoietic stem cell transplantation: getting closer to a cure? Blood 99:768–784CrossRefPubMedGoogle Scholar
  6. Calkoen FG, Brinkman DM, Vervat C et al (2013) Mesenchymal stromal cells isolated from children with systemic juvenile idiopathic arthritis suppress innate and adaptive immune responses. CytoTherapy 15:280–291CrossRefPubMedGoogle Scholar
  7. Cipriani P, Carubbi F, Liakouli V et al (2013) Stem cells in autoimmune diseases: Implications for pathogenesis and future trends in therapy. Autoimmun Rev 12:709–716CrossRefPubMedGoogle Scholar
  8. Colter DC, Class R, DiGirolamo CM et al (2000) Rapid expansion of recycling stem cells in cultures of plastic-adherent cells from human bone marrow. Proc Natl Acad Sci USA 97:3213–3218CrossRefPubMedGoogle Scholar
  9. Contreras RA, Figueroa FE, Djouad F et al (2016) Mesenchymal stem cells regulate the innate and adaptive immune responses dampening arthritis progression. Stem Cells Int 2016:3162743Google Scholar
  10. Deans RJ, Moseley AB (2000) Mesenchymal stem cells: biology and potential clinical uses. Exp Hematol 28:875–884CrossRefPubMedGoogle Scholar
  11. Di Nicola M, Carlo-Stella C, Magni M et al (2002) Human bone marrow stromal cells suppress T-lymphocyte proliferation induced by cellular or nonspecific mitogenic stimuli. Blood 99:3838–3843CrossRefPubMedGoogle Scholar
  12. Djouad F, Bony C, Haupl T et al (2005) Transcriptional profiles discriminate bone marrow-derived and synovium-derived mesenchymal stem cells. Arthritis Res Ther 7:R1304–R1315CrossRefPubMedPubMedCentralGoogle Scholar
  13. English K (2013) Mechanisms of mesenchymal stromal cell immunomodulation. Immunol Cell Biol 91:19–26CrossRefPubMedGoogle Scholar
  14. Friedenstein AJ, Chailakhyan RK, Latsinik NV et al (1974) Stromal cells responsible for transferring the microenvironment of the hemopoietic tissues. Cloning in vitro and retransplantation in vivo. Transplantation 17:331–340CrossRefPubMedGoogle Scholar
  15. Giancane G, Consolaro A, Lanni S et al (2016) Juvenile idiopathic arthritis: diagnosis and treatment. Rheumatol Ther 3:187–207CrossRefPubMedPubMedCentralGoogle Scholar
  16. Hahn YS, Kim JG (2010) Pathogenesis and clinical manifestations of juvenile rheumatoid arthritis. Korean J Pediatr 53:921–930CrossRefPubMedPubMedCentralGoogle Scholar
  17. Hinks A, Cobb J, Marion MC et al (2013) Dense genotyping of immune-related disease regions identifies 14 new susceptibility loci for juvenile idiopathic arthritis. Nat Genet 45:664–669CrossRefPubMedPubMedCentralGoogle Scholar
  18. Hou J, Ouyang Y, Deng H et al (2016) Whole-genome expression analysis and signal pathway screening of synovium-derived mesenchymal stromal cells in rheumatoid arthritis. Stem Cells Int 2016:1375031Google Scholar
  19. Huang JL (2012) New advances in juvenile idiopathic arthritis. Chang Gung Med J 35:1–14PubMedGoogle Scholar
  20. Jo CH, Lee YG, Shin WH et al (2014) Intra-articular injection of mesenchymal stem cells for the treatment of osteoarthritis of the knee: a proof-of-concept clinical trial. Stem Cells 32:1254–1266CrossRefPubMedGoogle Scholar
  21. Jorgensen C, Djouad F, Apparailly F et al (2003) Engineering mesenchymal stem cells for immunotherapy. Gene Ther 10:928–931CrossRefPubMedGoogle Scholar
  22. Kastrinaki MC, Sidiropoulos P, Roche S et al (2008) Functional, molecular and proteomic characterisation of bone marrow mesenchymal stem cells in rheumatoid arthritis. Ann Rheum Dis 67:741–749CrossRefPubMedGoogle Scholar
  23. MacFarlane RJ, Graham SM, Davies PS et al (2013) Anti-inflammatory role and immunomodulation of mesenchymal stem cells in systemic joint diseases: potential for treatment. Expert Opin Ther Targets 17:243–254CrossRefPubMedGoogle Scholar
  24. McInnes IB, Schett G (2007) Cytokines in the pathogenesis of rheumatoid arthritis. Nat Rev Immunol 7:429–442CrossRefPubMedGoogle Scholar
  25. Melief SM, Zwaginga JJ, Fibbe WE et al (2013) Adipose tissue-derived multipotent stromal cells have a higher immunomodulatory capacity than their bone marrow-derived counterparts. Stem Cells Transl Med 2:455–463CrossRefPubMedPubMedCentralGoogle Scholar
  26. Nemeth K, Leelahavanichkul A, Yuen PS et al (2009) Bone marrow stromal cells attenuate sepsis via prostaglandin E(2)-dependent reprogramming of host macrophages to increase their interleukin-10 production. Nat Med 15:42–49CrossRefPubMedGoogle Scholar
  27. Nie Y, Lau C, Lie A et al (2010) Defective phenotype of mesenchymal stem cells in patients with systemic lupus erythematosus. Lupus 19:850–859CrossRefPubMedGoogle Scholar
  28. Noel D, Djouad F, Jorgense C (2002) Regenerative medicine through mesenchymal stem cells for bone and cartilage repair. Curr Opin Investig Drugs 3:1000–1004PubMedGoogle Scholar
  29. Norambuena GA, Khoury M, Jorgensen C (2012) Mesenchymal stem cells in osteoarticular pediatric diseases: an update. Pediatr Res 71:452–458CrossRefPubMedGoogle Scholar
  30. Park MJ, Lee SH, Moon SJ et al (2016) Overexpression of soluble RAGE in mesenchymal stem cells enhances their immunoregulatory potential for cellular therapy in autoimmune arthritis. Sci Rep 6:35933CrossRefPubMedPubMedCentralGoogle Scholar
  31. Petty RE, Southwood TR, Manners P et al (2004) International League of Associations for Rheumatology classification of juvenile idiopathic arthritis: second revision, Edmonton, 2001. J Rheumatol 31:390–392PubMedGoogle Scholar
  32. Pittenger MF, Mackay AM, Beck SC et al (1999) Multilineage potential of adult human mesenchymal stem cells. Science 284:143–147CrossRefPubMedGoogle Scholar
  33. Ravelli A, Martini A (2007) Juvenile idiopathic arthritis. The Lancet 369:767–778CrossRefGoogle Scholar
  34. Shalev-Malul G, Soler DC, Ting AE et al (2016) Development of a functional biomarker for use in cell-based therapy studies in seropositive rheumatoid arthritis. Stem Cells Transl Med 5:628–6321CrossRefPubMedPubMedCentralGoogle Scholar
  35. Shin TH, Kim HS, Kang TW et al (2016) Human umbilical cord blood-stem cells direct macrophage polarization and block inflammasome activation to alleviate rheumatoid arthritis. Cell Death Dis 7:e2524CrossRefPubMedPubMedCentralGoogle Scholar
  36. Spaggiari GM, Capobianco A, Abdelrazik H et al (2008) Mesenchymal stem cells inhibit natural killer-cell proliferation, cytotoxicity, and cytokine production: role of indoleamine 2,3-dioxygenase and prostaglandin E2. Blood 111:1327–1333CrossRefPubMedGoogle Scholar
  37. Swart J, Martens A, Wulffraat N (2008) Mesenchymal stem cells: a future for the treatment of arthritis? Joint Bone Spine 75:379–382CrossRefPubMedGoogle Scholar
  38. Swart J, Wulffraat N, Prakken BJ et al (2015) Mesenchymal stromal cell treatment in juvenile idiopathic arthritis: a pilot study [abstract]. Arthritis Rheumatol 67:3813–3814Google Scholar
  39. Swidrowska-Jaros J, Orczyk K, Smolewska E (2016) Macrophages - silent enemies in juvenile idiopathic arthritis. Postepy Hig Med Dosw (Online) 70:743–750CrossRefGoogle Scholar
  40. Uccelli A, de Rosbo NK (2015) The immunomodulatory function of mesenchymal stem cells: mode of action and pathways. Ann N Y Acad Sci 1351:114–126CrossRefPubMedGoogle Scholar
  41. Verwoerd A, Ter Haar NM, de Roock S et al (2016) The human microbiome and juvenile idiopathic arthritis. Pediatr Rheumatol Online J 14:55CrossRefPubMedPubMedCentralGoogle Scholar
  42. Wakitani S, Okabe T, Horibe S et al (2011) Safety of autologous bone marrow-derived mesenchymal stem cell transplantation for cartilage repair in 41 patients with 45 joints followed for up to 11 years and 5 months. J Tissue Eng Regen Med 5:146–150CrossRefPubMedGoogle Scholar
  43. Wang L, Zhang Y, Li H et al (2016) Clinical observation of employment of umbilical cord derived mesenchymal stem cell for juvenile idiopathic arthritis therapy. Stem Cells Int 2016:9165267Google Scholar
  44. Wu CC, Liu FL, Sytwu HK et al (2016) CD146 + mesenchymal stem cells display greater therapeutic potential than CD146- cells for treating collagen-induced arthritis in mice. Stem Cell Res Ther 7:23CrossRefPubMedPubMedCentralGoogle Scholar
  45. Zhang Y, Khan D, Delling J et al (2012) Mechanisms underlying the osteo- and adipo-differentiation of human mesenchymal stem cells. Sci World J 2012:793823Google Scholar

Copyright information

© L. Hirszfeld Institute of Immunology and Experimental Therapy, Wroclaw, Poland 2017

Authors and Affiliations

  1. 1.Department of Pediatric RheumatologyMedical University of LodzLodzPoland

Personalised recommendations