Skip to main content
SpringerLink
Log in

Mesenchymal Stem Cell Therapy in Rheumatoid Arthritis

  • Chapter
  • First Online:
Bone and Cartilage Regeneration

Part of the book series: Stem Cells in Clinical Applications ((SCCA))

  • 963 Accesses

Abstract

Rheumatoid arthritis (RA) is the second most common form of arthritis and the most common inflammatory joint disorder in the UK, affecting more than 400,000 people with around 12,000 new cases diagnosed every year. The condition is chronic and degenerative, causing pain and swelling, stiffness and fatigue. The disorder affects females to males at a ratio of approximately 3:1 with an overall incidence of around 1 in 100. It is most commonly reported in people aged >40 years with most first diagnoses occurring at age <60 years and life expectancy may be reduced by up to 18 years. With such high prevalence, extensive work has been done to investigate causes, early diagnosis and treatments for RA, yet much about the disease remains elusive, no cure currently exists and treatment options are limited. Drug treatment and physiotherapy are first line approaches. Non-steroidal anti-inflammatory drugs (NSAIDs) and disease-modifying antirheumatic drugs (DMARDs) are common treatments. Recent research for novel treatments has led to the introduction of biological antibodies, such as anti-tumour necrosis factor alpha (anti-TNF-α). Whilst significant impact has been made in alleviating symptoms, 50 % of RA sufferers prescribed with biological treatments discontinue the use after 2 years due to declining efficacy or adverse side effects. In untreatable cases, the last resort is joint replacement. It is advantageous in treating multifaceted disorders to utilise a multifaceted therapy and mesenchymal stem cells (MSC) infusion offers this potential. This chapter reviews the application of mesenchymal stem cells in the treatment of RA and current research perspectives. The advantages of MSC therapies are discussed alongside evaluation of optimum models for use in in vivo testing of novel treatments. Outcomes of both preclinical and the few clinical trials conducted to date are discussed to develop both the potential and future of stem cell therapy for autoimmune conditions such as RA.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 139.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 179.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 179.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Similar content being viewed by others

Abbreviations

ADI:

After disease induction

ADO:

After disease onset

Anti-TNF-α:

Anti-tumour necrosis factor alpha

AT:

Adipose tissue

BM:

Bone marrow

CB:

Cord blood

DMARDs:

Disease-modifying antirheumatic drugs

HGF:

Hepatocyte growth factor

HO:

Hemoxygenase

IA:

Intra-articular

IDO:

Indoleamine 2,3-dioxygenase

IFN-γ:

Interferon gamma

IP:

Intraperitoneal

IV:

Intravenous

MSC:

Mesenchymal stem cells

NSAIDs:

Non-steroidal anti-inflammatory drugs

PDGF:

Platelet-derived growth factor

PDO:

Pre-disease onset

PGE2:

Prostaglandin E2

RA:

Rheumatoid arthritis

RANKL:

Receptor activator of nuclear factor kappa-β ligand

SF:

Synovial fluid

TGF-β1:

Transforming growth factor type 1

VEGF:

Vascular endothelial growth factor

References

  • Abdallah BM, Kassem M. The use of mesenchymal (skeletal) stem cells for treatment of degenerative diseases: current status and future perspectives. J Cell Physiol. 2009;218(1):9–12. Review.

    Article  CAS  PubMed  Google Scholar 

  • Acuff HB, Carter KJ, Fingleton B, Gorden DL, Matrisian LM. Matrix metalloproteinase-9 from bone marrow-derived cells contributes to survival but not growth of tumor cells in the lung microenvironment. Cancer Res. 2006;66(1):259–66.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Alvaro-Gracia JM, Jover JA, Garcia-Vicuña R, Carreño L, Alonso A, Marsal S, et al. Phase IB/Iia study on intravenous administration of expanded allogeneic adipose-derived mesenchymal stem cells in refractory rheumatoid arthritis patients (abstract). Arthritis Rheum. 2013;65(Suppl 10):2644. doi:10.1002/art.2013.65.issue-s10.

  • Aruffo A, Stamenkovic I, Melnick M, Underhill CB, Seed B. CD44 is the principal cell surface receptor for hyaluronate. Cell. 1990;61(7):1303–13.

    Article  CAS  PubMed  Google Scholar 

  • Asquith DL, Miller AM, McInnes IB, Liew FY. Animal models of rheumatoid arthritis. Eur J Immunol. 2009;39(8):2040–4. doi:10.1002/eji.200939578.

    Article  CAS  PubMed  Google Scholar 

  • Augello A, Tasso R, Negrini SM, Cancedda R, Pennesi G. Cell therapy using allogeneic bone marrow mesenchymal stem cells prevents tissue damage in collagen-induced arthritis. Arthritis Rheum. 2007;56:1175–86.

    Article  CAS  PubMed  Google Scholar 

  • Augello A, Kurth TB, De Bari C. Mesenchymal stem cells: a perspective from in vitro cultures to in vivo migration and niches. Eur Cell Mater. 2010;20:121–33.

    Article  CAS  PubMed  Google Scholar 

  • Baddack U, et al. A chronic model of arthritis supported by a strain-specific periarticular lymph node in BALB/c mice. Nat Commun. 2013;4:1644. doi:10.1038/ncomms2625.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Baksh D, Yao R, Tuan RS. Comparison of proliferative and multilineage differentiation potential of human mesenchymal stem cells derived from umbilical cord and bone marrow. Stem Cells. 2007;25:1384–92.

    Article  CAS  PubMed  Google Scholar 

  • Bartholomew A, Sturgeon C, Siatskas M, Ferrer K, McIntosh K, Patil S, Hardy W, Devine S, Ucker D, Deans R, Moseley A, Hoffman R. Mesenchymal stem cells suppress lymphocyte proliferation in vitro and prolong skin graft survival in vivo. Exp Hematol. 2002;30(1):42–8.

    Article  PubMed  Google Scholar 

  • Berger A. Th1 and Th2 responses: what are they? BMJ. 2000;321(7258):424.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bernardo ME, Fibbe WE. Mesenchymal stromal cells: sensors and switchers of inflammation. Cell Stem Cell. 2013;13(4):392–402. doi:10.1016/j.stem.2013.09.006. Review.

    Article  CAS  PubMed  Google Scholar 

  • Bi Y, Ehi rchiou D, Kilts TM, Inkson CA, Embree MC, Sonoyama W, Li L, Leet AI, Seo BM, Zhang L, Shi S, Young MF. Identification of tendon stem/progenitor cells and the role of the extracellular matrix in their niche. Nat Med. 2007;13:1219–27.

    Google Scholar 

  • Binger T, Stich S, Andreas K, Kaps C, Sezer O, Notter M, Sittinger M, Ringe J. Migration potential and gene expression profile of human mesenchymal stem cells induced by CCL25. Exp Cell Res. 2009;315(8):1468–79. doi:10.1016/j.yexcr.2008.12.022.

    Article  CAS  PubMed  Google Scholar 

  • Bonab MM, Alimoghaddam K, Talebian F, Ghaffari SH, Ghavamzadeh A, Nikbin B. Aging of mesenchymal stem cell in vitro. BMC Cell Biol. 2006;7:14.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Bosnakovski D, Mizuno M, Kim G, Ishiguro T, Okumura M, Iwanaga T, Kadosawa T, Fujinaga T. Chondrogenic differentiation of bovine bone marrow mesenchymal stem cells in pellet cultural system. Exp Hematol. 2004;32(5):502–9.

    Article  CAS  PubMed  Google Scholar 

  • Bosnakovski D, Mizuno M, Kim G, Takagi S, Okumur M, Fujinag T. Gene expression profile of bovine bone marrow mesenchymal stem cell during spontaneous chondrogenic differentiation in pellet culture system. Jpn J Vet Res. 2006;53(3-4):127–39.

    PubMed  Google Scholar 

  • Bouffi C, Bony C, Courties G, Jorgensen C, Noel D. IL-6-dependent PGE2 secretion by mesenchymal stem cells inhibits local inflammation in experimental arthritis. PLoS One. 2010;5, e14247.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Brackertz D, Mitchell GF, Mackay IR. Antigen-induced arthritis in mice. I. Induction of arthritis in various strains of mice. Arthritis Rheum. 1977;20(3):841–50. doi:10.1002/art.1780200314.

    Article  CAS  PubMed  Google Scholar 

  • Brand DD, Latham KA, Rosloniec EF. Collagen-induced arthritis. Nat Protoc. 2007;2(5):1269–75. doi:10.1038/nprot.2007.173.

    Article  CAS  PubMed  Google Scholar 

  • Brooks DJ. Positron emission tomography and single-photon emission computed tomography in central nervous system drug development. NeuroRx. 2005;2(2):226–36. Review.

    Article  PubMed  PubMed Central  Google Scholar 

  • Campbell DJ, Kim CH, Butcher EC. Chemokines in the systemic organization of immunity. Immunol Rev. 2003;195:58–71. Review.

    Article  CAS  PubMed  Google Scholar 

  • Cannella AC, O’Dell JR. Traditional DMARDs: methotrexate, leflunomide, sulfasalazine, hydroxychloroquine, and combination therapies. In: Kelly’s textbook of rheumatology. 9th ed. Philadelphia PA: Elsevier Saunders; 2013.

    Google Scholar 

  • Chen B, Hu J, Liao L, Sun Z, Han Q, Song Z, et al. Flk-1 mesenchymal stem cells aggravate collagen-induced arthritis by up-regulating interleukin-6. Clin Exp Immunol. 2010;159:292–302.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Choi JJ, Yoo SA, Park SJ, Kang YJ, Kim WU, Oh IH, et al. Mesenchymal stem cells overexpressing interleukin-10 attenuate collagen-induced arthritis in mice. Clin Exp Immunol. 2008;153:269–76.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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, Corazza GR. Autologous bone marrow-derived mesenchymal stromal cells in the treatment of fistulising Crohn’s disease. Gut. 2011;60(6):788–98. doi:10.1136/gut.2010.214841.

    Article  PubMed  Google Scholar 

  • Civatte M, Bartoli C, Schleinitz N, Chetaille B, Pellissier JF, Figarella-Branger D. Expression of the beta chemokines CCL3, CCL4, CCL5 and their receptors in idiopathic inflammatory myopathies. Neuropathol Appl Neurobiol. 2005;31(1):70–9.

    Article  CAS  PubMed  Google Scholar 

  • Colter DC, Class R, DiGirolamo CM, Prockop DJ. Rapid expansion of recycling stem cells in cultures of plastic-adherent cells from human bone marrow. Proc Natl Acad Sci U S A. 2000;97(7):3213–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Connick P, Kolappan M, Crawley C, Webber DJ, Patani R, Michell AW, Du MQ, Luan SL, Altmann DR, Thompson AJ, Compston A, Scott MA, Miller DH, Chandran S. Autologous mesenchymal stem cells for the treatment of secondary progressive multiple sclerosis: an open-label phase 2a proof-of-concept study. Lancet Neurol. 2012;11(2):150–6. doi:10.1016/S1474-4422(11)70305-2.

    Article  PubMed  PubMed Central  Google Scholar 

  • Crisan M, Yap S, Casteilla L, et al. A perivascular origin for mesenchymal stem cells in multiple human organs. Cell Stem Cell. 2008;3:301–13.

    Google Scholar 

  • da Silva Meirelles L, Chagastelles PC, Nardi NB. Mesenchymal stem cells reside in virtually all post-natal organs and tissues. J Cell Sci. 2006;119:2204–13.

    Article  PubMed  CAS  Google Scholar 

  • De Bari C. Are mesenchymal stem cells in rheumatoid arthritis the good or bad guys? Arthritis Res Ther. 2015;17(1):113. doi:10.1186/s13075-015-0634-1.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • De Bari C, Dell’Accio F, Tylzanowski P, Luyten FP. Multipotent mesenchymal stem cells from adult human synovial membrane. Arthritis Rheum. 2001;44:1928–42.

    Article  PubMed  Google Scholar 

  • De Becker A, Van Hummelen P, Bakkus M, Vande Broek I, De Wever J, De Waele M, Van Riet I. Migration of culture-expanded human mesenchymal stem cells through bone marrow endothelium is regulated by matrix metalloproteinase-2 and tissue inhibitor of metalloproteinase-3. Haematologica. 2007;92:440–9.

    Article  PubMed  Google Scholar 

  • Dejana E, Orsenigo F, Lampugnani MG. The role of adherens junctions and VE-cadherin in the control of vascular permeability. J Cell Sci. 2008;121(Pt 13):2115–22. Review, doi:10.1242/jcs.017897.

    Google Scholar 

  • Djouad F, Fritz V, Apparailly F, Louis-Plence P, Bony C, Sany J, et al. Reversal of the immunosuppressive properties of mesenchymal stem cells by tumor necrosis factor in collagen-induced arthritis. Arthritis Rheum. 2005;52:1595–603.

    Article  CAS  PubMed  Google Scholar 

  • Doeing DC, Borowicz JL, Crockett ET. Gender dimorphism in differential peripheral blood leukocyte counts in mice using cardiac, tail, foot, and saphenous vein puncture methods. BMC Clin Pathol. 2003;3:3.

    Article  PubMed  PubMed Central  Google Scholar 

  • Dominici M, Le Blanc K, Mueller I, et al. Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy. 2006;8:315–7.

    Article  CAS  PubMed  Google Scholar 

  • Duijvestein M, Vos AC, Roelofs H, Wildenberg ME, Wendrich BB, Verspaget HW, Kooy-Winkelaar EM, Koning F, Zwaginga JJ, Fidder HH, Verhaar AP, Fibbe WE, van den Brink GR, Hommes DW. Autologous bone marrow-derived mesenchymal stromal cell treatment for refractory luminal Crohn’s disease: results of a phase I study. Gut. 2010;59(12):1662–9. doi:10.1136/gut.2010.215152.

    Article  PubMed  Google Scholar 

  • Eirin A, Zhu XY, Krier JD, et al. Adipose tissue-derived mesenchymal stem cells improve revascularization outcomes to restore renal function in swine atherosclerotic renal artery stenosis. Stem Cells. 2012;30:1030–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Eseonu OI, De Bari C. Homing of mesenchymal stem cells: mechanistic or stochastic? Implications for targeted delivery in arthritis. Rheumatology (Oxford). 2015;54(2):210–8. doi:10.1093/rheumatology/keu377. Epub 2014 Oct 6. Review.

    Article  Google Scholar 

  • Feldmann M, Maini RN. Lasker clinical medical research award. TNF defined as a therapeutic target for rheumatoid arthritis and other autoimmune diseases. Nat Med. 2003;9(10):1245–50.

    Article  CAS  PubMed  Google Scholar 

  • Finnegan A, Mikecz K, Tao P, Glant TT. Proteoglycan (aggrecan)-induced arthritis in BALB/c mice is a Th1-type disease regulated by Th2 cytokines. J Immunol. 1999;163(10):5383–90.

    CAS  PubMed  Google Scholar 

  • Firestein GS. Evolving concepts of rheumatoid arthritis. Nature. 2003;423:356–61.

    Article  CAS  PubMed  Google Scholar 

  • Foulquier C, Sebbag M, Clavel C, Chapuy-Regaud S, Al Badine R, Méchin MC, Vincent C, Nachat R, Yamada M, Takahara H, Simon M, Guerrin M, Serre G. Peptidyl arginine deiminase type 2 (PAD-2) and PAD-4 but not PAD-1, PAD-3, and PAD-6 are expressed in rheumatoid arthritis synovium in close association with tissue inflammation. Arthritis Rheum. 2007;56(11):3541–53.

    Article  CAS  PubMed  Google Scholar 

  • Friedenstein AJ, Deriglasova UF, Kulagina NN, Panasuk AF, Rudakowa SF, Luriá EA, Ruadkow IA. Precursors for fibroblasts in different populations of hematopoietic cells as detected by the in vitro colony assay method. Exp Hematol. 1974;2(2):83–92.

    CAS  PubMed  Google Scholar 

  • Friedenstein AJ, Gorskaja JF, Kulagina NN. Fibroblast precursors in normal and irradiated mouse hematopoietic organs. Exp Hematol. 1976;4(5):267–74.

    CAS  PubMed  Google Scholar 

  • Fukuchi Y, Nakajima H, Sugiyama D, et al. Human placenta-derived cells have mesenchymal stem/progenitor cell potential. Stem Cells. 2004;22:649–58.

    Google Scholar 

  • Gangji V, Hauzeur JP, Matos C, De MV, Toungouz M, Lambermont M. Treatment of osteonecrosis of the femoral head with implantation of autologous bone-marrow cells: a pilot study. J Bone Joint Surg Am. 2004;86-A(6):1153–60.

    Article  PubMed  Google Scholar 

  • Ge J, et al. The size of mesenchymal stem cells is a significant cause of vascular obstructions and stroke. Stem Cell Rev. 2014;10(2):295–303. doi:10.1007/s12015-013-9492-x.

    Article  CAS  PubMed  Google Scholar 

  • Gonzalez MA, Gonzalez-Rey E, Rico L, Buscher D, Delgado M. Treatment of experimental arthritis by inducing immune tolerance with human adipose-derived mesenchymal stem cells. Arthritis Rheum. 2009;60:1006–19.

    Article  CAS  PubMed  Google Scholar 

  • Grogan SP, Barbero A, Diaz-Romero J, Cleton-Jansen AM, Soeder S, Whiteside R, Hogendoorn PC, Farhadi J, Aigner T, Martin I, Mainil-Varlet P. Identification of markers to characterize and sort human articular chondrocytes with enhanced in vitro chondrogenic capacity. Arthritis Rheum. 2007;56(2):586–95.

    Article  PubMed  Google Scholar 

  • Gronthos S, Mankani M, Brahim J, Robey PG, Shi S. Postnatal human dental pulp stem cells (DPSCs) in vitro and in vivo. Proc Natl Acad Sci U S A. 2000;97:13625–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hagmann S, Moradi B, Frank S, Dreher T, Kämmerer PW, Richter W, Gotterbarm T. FGF-2 addition during expansion of human bone marrow-derived stromal cells alters MSC surface marker distribution and chondrogenic differentiation potential. Cell Prolif. 2013;46(4):396–407. doi:10.1111/cpr.12046.

    Article  CAS  PubMed  Google Scholar 

  • Hermida-Gomez T, Fuentes-Boquete I, Gimeno-Longas MJ, et al. Quantification of cells expressing mesenchymal stem cell markers in healthy and osteoarthritic synovial membranes. J Rheumatol. 2011;38:339–49.

    Article  PubMed  Google Scholar 

  • Honczarenko M, Le Y, Swierkowski M, Ghiran I, Glodek AM, Silberstein LE. Human bone marrow stromal cells express a distinct set of biologically functional chemokine receptors. Stem Cells. 2006;24(4):1030–41.

    Article  CAS  PubMed  Google Scholar 

  • Huang GT, Gronthos S, Shi S. Mesenchymal stem cells derived from dental tissues vs. those from other sources: their biology and role in regenerative medicine. J Dent Res. 2009;88:792–806.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Iyer SS, Rojas M. Anti-inflammatory effects of mesenchymal stem cells: novel concept for future therapies. Expert Opin Biol Ther. 2008;8(5):569–81. doi:10.1517/14712598.8.5.569.

    Article  CAS  PubMed  Google Scholar 

  • Kay A, Richardson J, Forsyth NR. Physiological normoxia and chondrogenic potential of chondrocytes. Front Biosci (Elite Ed). 2011;3:1365–74.

    Google Scholar 

  • Kehoe O, Cartwright A, Askari A, El Haj AJ, Middleton J. Intra-articular injection of mesenchymal stem cells leads to reduced inflammation and cartilage damage in murine antigen-induced arthritis. J Transl Med. 2014;12:157. doi:10.1186/1479-5876-12-157.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Kim CH, Rott L, Kunkel EJ, Genovese MC, Andrew DP, Wu L, Butcher EC. Rules of chemokine receptor association with T cell polarization in vivo. J Clin Invest. 2001;108(9):1331–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kleinau S, Dencker L, Klareskog L. Oil-induced arthritis in DA rats: tissue distribution of arthritogenic 14C-labelled hexadecane. Int J Immunopharmacol. 1995;17(5):393–401. doi:10.1016/0192-0561(95)00020-3.

    Article  CAS  PubMed  Google Scholar 

  • Koga T, et al. Acute joint inflammation in mice after systemic injection of the cell wall, its peptidoglycan, and chemically defined peptidoglycan subunits from various bacteria. Infect Immun. 1985;50(1):27–34.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Kokkonen H, Söderström I, Rocklöv J, Hallmans G, Lejon K, Dahlqvist Rantapää S. Up-regulation of cytokines and chemokines predates the onset of rheumatoid arthritis. Arthritis Rheum. 2010;62(2):383–91. doi:10.1002/art.27186.

    CAS  PubMed  Google Scholar 

  • Kouskoff V, Korganow AS, Duchatelle V, Degott C, Benoist C, Mathis D. Organ-specific disease provoked by systemic autoimmunity. Cell. 1996;87(5):811–22. doi:10.1016/S0092-8674(00)81989-3.

    Article  CAS  PubMed  Google Scholar 

  • 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, Fibbe W, Ringdén O, Developmental Committee of the European 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. 2008;371(9624):1579–86. doi:10.1016/S0140-6736(08)60690-X.

    Article  PubMed  CAS  Google Scholar 

  • Lee WJ, Hah YS, Ock SA, Lee JH, Jeon RH, Park JS, Lee SI, Rho NY, Rho GJ, Lee SL. Cell source-dependent in vivo immunosuppressive properties of mesenchymal stem cells derived from the bone marrow and synovial fluid of minipigs. Exp Cell Res. 2015;333(2):273–88. doi:10.1016/j.yexcr.2015.03.015.

    Article  CAS  PubMed  Google Scholar 

  • Ley K, Laudanna C, Cybulsky MI, Nourshargh S. Getting to the site of inflammation: the leukocyte adhesion cascade updated. Nat Rev Immunol. 2007;7(9):678–89. Review.

    Article  CAS  PubMed  Google Scholar 

  • Liang J, Zhang H, Hua B, Wang H, Lu L, Shi S, Hou Y, Zeng X, Gilkeson GS, Sun L. Allogenic mesenchymal stem cells transplantation in refractory systemic lupus erythematosus: a pilot clinical study. Ann Rheum Dis. 2010;69(8):1423–9. doi:10.1136/ard.2009.123463. Erratum in: Ann Rheum Dis. 2011;70(1):237.

    Google Scholar 

  • Liu Y, Mu R, Wang S, Long L, Liu X, Li R, et al. Therapeutic potential of human umbilical cord mesenchymal stem cells in the treatment of rheumatoid arthritis. Arthritis Res Ther. 2010;12:R210.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Liu H, Ding J, Wang J, Wang Y, Yang M, Zhang Y, Chang F, Chen X. Remission of collagen-induced arthritis through combination therapy of microfracture and transplantation of thermogel-encapsulated bone marrow mesenchymal stem cells. PLoS One. 2015;10(3), e0120596. doi:10.1371/journal.pone.0120596.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Ma S, Xie N, Li W, Yuan B, Shi Y, Wang Y. Immunobiology of mesenchymal stem cells. Cell Death Differ. 2014;21(2):216–25. doi:10.1038/cdd.2013.158. Review.

    Article  CAS  PubMed  Google Scholar 

  • MacDonald GI, Augello A, De Bari C. Role of mesenchymal stem cells in reestablishing immunologic tolerance in autoimmune rheumatic diseases. Arthritis Rheum. 2011;63(9):2547–57. doi:10.1002/art.30474.

    Article  CAS  PubMed  Google Scholar 

  • Mao F, Xu WR, Qian H, Zhu W, Yan YM, Shao QX, Xu HX. Immunosuppressive effects of mesenchymal stem cells in collagen-induced mouse arthritis. Inflamm Res. 2010;59(3):219–25. doi:10.1007/s00011-009-0090-y.

    Article  CAS  PubMed  Google Scholar 

  • Marhaba R, Zöller M. CD44 in cancer progression: adhesion, migration and growth regulation. J Mol Histol. 2004;35(3):211–31. Review.

    Article  CAS  PubMed  Google Scholar 

  • Markides H, Kehoe O, Morris RH, El Haj AJ. Whole body tracking of superparamagnetic iron oxide nanoparticle-labelled cells–a rheumatoid arthritis mouse model. Stem Cell Res Ther. 2013;17;4(5):126. doi:10.1186/scrt337.

    Google Scholar 

  • Martin-Rendon E, Sweeney D, Lu F, et al. 5-Azacytidine-treated human mesenchymal stem/progenitor cells derived from umbilical cord, cord blood and bone marrow do not generate cardiomyocytes in vitro at high frequencies. Vox Sang. 2008;95:137–48.

    Article  CAS  PubMed  Google Scholar 

  • McInnes IB, Schett G. Cytokines in the pathogenesis of rheumatoid arthritis. Nat Rev Immunol. 2007;7(6):429–42. Review.

    Article  CAS  PubMed  Google Scholar 

  • McInnes IB, Schett G. The pathogenesis of rheumatoid arthritis. N Engl J Med. 2011;365(23):2205–19. doi:10.1056/NEJMra1004965. Review.

    Article  CAS  PubMed  Google Scholar 

  • Mestas J, Hughes CC. Of mice and not men: differences between mouse and human immunology. J Immunol. 2004;172(5):2731–8. Review.

    Article  CAS  PubMed  Google Scholar 

  • Middleton J, et al. Endothelial cell phenotypes in the rheumatoid synovium: activated, angiogenic, apoptotic and leaky. Arthritis Res Ther. 2004;6(2):60–72. doi:10.1186/ar1156.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Monach PA, Mathis D, Benoist C. The K/BxN arthritis model. Curr Protoc Immunol. 2008. doi:10.1002/0471142735.

  • Naor D, Sionov RV, Ish-Shalom D. CD44: structure, function, and association with the malignant process. Adv Cancer Res. 1997;71:241–319. Review.

    Article  CAS  PubMed  Google Scholar 

  • Nasef A, Ashammakhi N, Fouillard L. Immunomodulatory effect of mesenchymal stromal cells: possible mechanisms. Regen Med. 2008;3(4):531–46.

    Article  CAS  PubMed  Google Scholar 

  • Naylor AJ, Filer A, Buckley CD. The role of stromal cells in the persistence of chronic inflammation. Clin Exp Immunol. 2013;171:30–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Newman RE, Yoo D, LeRoux MA, Danilkovitch-Miagkova A. Treatment of inflammatory diseases with mesenchymal stem cells. Inflamm Allergy Drug Targets. 2009;8(2):110–23. doi:10.2174/187152809788462635.

    Article  CAS  PubMed  Google Scholar 

  • Nomura T, Honmou O, Harada K, Houkin K, Hamada H, Kocsis JD. I.V. infusion of brain-derived neurotrophic factor gene-modified human mesenchymal stem cells protects against injury in a cerebral ischemia model in adult rat. Neuroscience. 2005;136:161–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nöth U, Osyczka AM, Tuli R, Hickok NJ, Danielson KG, Tuan RS. Multilineage mesenchymal differentiation potential of human trabecular bone-derived cells. J Orthop Res. 2002;20:1060–9.

    Article  PubMed  Google Scholar 

  • Nowell MA, et al. Soluble IL-6 receptor governs IL-6 activity in experimental arthritis: blockade of arthritis severity by soluble glycoprotein 130. J Immunol. 2003;171(6):3202–9. doi:10.4049/jimmunol.171.6.3202.

    Article  CAS  PubMed  Google Scholar 

  • Oliver JE, Silman AJ. Risk factors for the development of rheumatoid arthritis. Scand J Rheumatol. 2006;35(3):169–74. Review.

    Article  CAS  PubMed  Google Scholar 

  • Oliver JE, Silman AJ. What epidemiology has told us about risk factors and aetiopathogenesis in rheumatic diseases. Arthritis Res Ther. 2009;11(3):223.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Ortmann RA, Shevach EM. Susceptibility to collagen-induced arthritis: cytokine-mediated regulation. Clin Immunol. 2001;98(1):109–18. doi:10.1006/clim.2000.4961.

    Article  CAS  PubMed  Google Scholar 

  • Papadopoulou A, Yiangou M, Athanasiou E, Zogas N, Kaloyannidis P, Batsis I, Fassas A, Anagnostopoulos A, Yannaki E. Mesenchymal stem cells are conditionally therapeutic in preclinical models of rheumatoid arthritis. Ann Rheum Dis. 2012;71(10):1733–40. doi:10.1136/annrheumdis-2011-200985.

    Article  PubMed  Google Scholar 

  • Park JC, Kim JM, Jung IH, et al. Isolation and characterization of human periodontal ligament (PDL) stem cells (PDLSCs) from the inflamed PDL tissue: in vitro and in vivo evaluations. J Clin Periodontol. 2011a;38:721–31.

    Article  PubMed  Google Scholar 

  • Park MJ, Park HS, Cho ML, Oh HJ, Cho YG, Min SY, et al. Transforming growth factor–transduced mesenchymal stem cells ameliorate autoimmune arthritis through reciprocal regulation of Treg/Th17 cells and osteoclastogenesis. Arthritis Rheum. 2011b;63:1668–80.

    Article  CAS  PubMed  Google Scholar 

  • Park JS, Suryaprakash S, Lao YH, Leong KW. Engineering mesenchymal stem cells for regenerative medicine and drug delivery. Methods. 2015;S1046-2023(15)00096-1. doi:10.1016/j.ymeth.2015.03.002.

    Google Scholar 

  • Park KH, Mun CH, Kang MI, Lee SW, Lee SK, Park YB. Treatment of collagen-induced arthritis using immune modulatory properties of human mesenchymal stem cells. Cell Transplant. 2016;25(6):1057–72. doi:10.3727/096368915X687949. Epub 2015 Apr 7.

    Google Scholar 

  • Peister A, Mellad JA, Larson BL, Hall BM, Gibson LF, Prockop DJ. Adult stem cells from bone marrow (MSCs) isolated from different strains of inbred mice vary in surface epitopes, rates of proliferation, and differentiation potential. Blood. 2004;103(5):1662–8. doi:10.1182/blood-2003-09-3070.

    Article  CAS  PubMed  Google Scholar 

  • Pettifer ER, Blake S. Antigen induced arthritis. In: Henderson B, Edwards JCW, Pettipher ER, editors. Mechanisms and models in rheumatoid arthritis. London: Academic; 1995.

    Google Scholar 

  • Pincus T, Kavanaugh A, Sokka T. Benefit/risk of therapies for rheumatoid arthritis: underestimation of the “side effects” or risks of RA leads to underestimation of the benefit/risk of therapies. Clin Exp Rheumatol. 2004;22(5 Suppl 35):S2–11. Review.

    CAS  PubMed  Google Scholar 

  • Pittenger MF, Mackay AM, Beck SC, Jaiswal RK, Douglas R, Mosca JD, Moorman MA, Simonetti DW, Craig S, Marshak DR. Multilineage potential of adult human mesenchymal stem cells. Science. 1999;284:143–7.

    Article  CAS  PubMed  Google Scholar 

  • Ponta H, Sherman L, Herrlich PA. CD44: from adhesion molecules to signalling regulators. Nat Rev Mol Cell Biol. 2003 Jan; 4(1):33–45.

    Google Scholar 

  • Ries C, Egea V, Karow M, Kolb H, Jochum M, Neth P. MMP-2, MT1-MMP, and TIMP-2 are essential for the invasive capacity of human mesenchymal stem cells: differential regulation by inflammatory cytokines. Blood. 2007;109:4055–63.

    Article  CAS  PubMed  Google Scholar 

  • Romanov YA, Svintsitskaya VA, Smirnov VN. Searching for alternative sources of postnatal human mesenchymal stem cells: candidate MSC-like cells from umbilical cord. Stem Cells. 2003;21:105–10.

    Article  PubMed  Google Scholar 

  • Rubbert-Roth A, Finckh A. Treatment options in patients with rheumatoid arthritis failing initial TNF inhibitor therapy: a critical review. Arthritis Res Ther. 2009;11(Suppl 1):S1. doi:10.1186/ar2666. Review.

    Google Scholar 

  • Ryu CH, Park SA, Kim SM, Lim JY, Jeong CH, Jun JA, Oh JH, Park SH, Oh WI, Jeun SS. Migration of human umbilical cord blood mesenchymal stem cells mediated by stromal cell-derived factor-1/CXCR4 axis via Akt, ERK, and p38 signal transduction pathways. Biochem Biophys Res Commun. 2010;398:105–10.

    Article  CAS  PubMed  Google Scholar 

  • Sarugaser R, Lickorish D, Baksh D, et al. Human umbilical cord perivascular (HUCPV) cells: a source of mesenchymal progenitors. Stem Cells. 2005;23:220–9.

    Article  PubMed  Google Scholar 

  • Schett G, Stolina M, Dwyer D, Zack D, Uderhardt S, Krönke G, Kostenuik P, Feige U. Tumor necrosis factor alpha and RANKL blockade cannot halt bony spur formation in experimental inflammatory arthritis. Arthritis Rheum. 2009;60(9):2644–54. doi:10.1002/art.24767.

    Article  CAS  PubMed  Google Scholar 

  • Schrepfer S, Deuse T, Reichenspurner H, Fischbein MP, Robbins RC, Pelletier MP. Stem cell transplantation: the lung barrier. Transplant Proc. 2007;39:573–6.

    Article  CAS  PubMed  Google Scholar 

  • Schurgers E, Kelchtermans H, Mitera T, Geboes L, Matthys P. Discrepancy between the in vitro and in vivo effects of murine mesenchymal stem cells on T-cell proliferation and collagen induced arthritis. Arthritis Res Ther. 2010;12:R31.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Schwab KE, Hutchinson P, Gargett CE. Identification of surface markers for prospective isolation of human endometrial stromal colony-forming cells. Hum Reprod. 2008;23:934–43.

    Article  CAS  PubMed  Google Scholar 

  • Sherwood J, Bertrand J, Nalesso G, Poulet B, Pitsillides A, Brandolini L, Karystinou A, De Bari C, Luyten FP, Pitzalis C, Pap T, Dell’Accio F. A homeostatic function of CXCR2 signalling in articular cartilage. Ann Rheum Dis. 2014. doi: 10.1136/annrheumdis-2014-205546.

    Google Scholar 

  • Shu J, Pan L, Huang X, Wang P, Li H, He X, Cai Z. Transplantation of human amnion mesenchymal cells attenuates the disease development in rats with collagen-induced arthritis. Clin Exp Rheumatol. 2015 Jul–Aug;33(4):484–90. Epub 2015 May 11.

    Google Scholar 

  • Stanton H, Rogerson FM, East CJ, Golub SB, Lawlor KE, Meeker CT, Little CB, Last K, Farmer PJ, Campbell IK, Fourie AM, Fosang AJ. ADAMTS5 is the major aggrecanase in mouse cartilage in vivo and in vitro. Nature. 2005;434(7033):648–52. doi:10.1038/nature03417.

    Article  CAS  PubMed  Google Scholar 

  • Stanton H, Golub SB, Rogerson FM, Last K, Little CB, Fosang AJ. Investigating ADAMTS-mediated aggrecanolysis in mouse cartilage. Nat Protoc. 2011;6(3):388–404. doi:10.1038/nprot.2010.179.

    Article  CAS  PubMed  Google Scholar 

  • Sudres M, Norol F, Trenado A, Grégoire S, Charlotte F, Levacher B, Lataillade JJ, Bourin P, Holy X, Vernant JP, Klatzmann D, Cohen JL. Bone marrow mesenchymal stem cells suppress lymphocyte proliferation in vitro but fail to prevent graft-versus-host disease in mice. J Immunol. 2006;176(12):7761–7.

    Article  CAS  PubMed  Google Scholar 

  • Sullivan C, Murphy JM, Griffin MD, Porter RM, Evans CH, O’Flatharta C, Shaw G, Barry F. Genetic mismatch affects the immunosuppressive properties of mesenchymal stem cells in vitro and their ability to influence the course of collagen-induced arthritis. Arthritis Res Ther. 2012;14(4):R167. doi:10.1186/ar3916.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Symmons D, et al. The prevalence of rheumatoid arthritis in the United Kingdom: new estimates for a new century. Rheumatology. 2002;41(7):793–800. doi:10.1093/rheumatology/41.7.793.

    Article  CAS  PubMed  Google Scholar 

  • Tondreau T, Meuleman N, Delforge A, et al. Mesenchymal stem cells derived from CD133-positive cells in mobilized peripheral blood and cord blood: proliferation, Oct4 expression, and plasticity. Stem Cells. 2005;23:1105–12.

    Article  CAS  PubMed  Google Scholar 

  • van den Berg WB. What we learn from arthritis models to benefit arthritis patients. Bailliere’s Clin Rheumatol. 2000;14(4):599–616. doi:10.1053/berh.2000.0102.

    Article  Google Scholar 

  • van den Berg WB, van Lent PL, Joosten LA, Abdollahi-Roodsaz S, Koenders MI. Amplifying elements of arthritis and joint destruction. Ann Rheum Dis. 2007 Nov;66 Suppl 3:iii45–8.

    Google Scholar 

  • van Lent PL, et al. Role of Fc receptor gamma chain in inflammation and cartilage damage during experimental antigen-induced arthritis. Arthritis Rheum. 2000;43(4):740–52. doi:10.1002/1529-0131(200004)43:4<740::AID-ANR4>3.0.CO;2-0.

    Article  PubMed  Google Scholar 

  • Wang H, Wu M, Liu Y. Are mesenchymal stem cells major sources of safe signals in immune system? Cell Immunol. 2012;272(2):112–6. doi:10.1016/j.cellimm.2011.10.010. Epub 2011 Oct 29. Review.

    Article  CAS  PubMed  Google Scholar 

  • Wang L, et al. Human umbilical cord mesenchymal stem cell therapy for patients with active rheumatoid arthritis: safety and efficacy. Stem Cells Dev. 2013;22(24):3192–202. doi:10.1089/scd.2013.0023.

    Article  CAS  PubMed  Google Scholar 

  • Wang D, Li J, Zhang Y, Zhang M, Chen J, Li X, Hu X, Jiang S, Shi S, Sun L. Umbilical cord mesenchymal stem cell transplantation in active and refractory systemic lupus erythematosus: a multicenter clinical study. Arthritis Res Ther. 2014;16(2):R79. doi:10.1186/ar4520.

    Article  PubMed  PubMed Central  Google Scholar 

  • Wiles N, et al. Estimating the incidence of rheumatoid arthritis – trying to hit a moving target? Arthritis Rheum. 1999;42(7):1339–46. doi:10.1002/1529-0131(199907)42:7<1339::AID-ANR6>3.0.CO;2-Y.

    Article  CAS  PubMed  Google Scholar 

  • Wong PK, Quinn JM, Sims NA, van Nieuwenhuijze A, Campbell IK, Wicks IP. Interleukin-6 modulates production of T lymphocyte-derived cytokines in antigen-induced arthritis and drives inflammation-induced osteoclastogenesis. Arthritis Rheum. 2006;54(1):158–68. doi:10.1002/art.21537.

    Article  CAS  PubMed  Google Scholar 

  • Zuk PA, Zhu M, Ashjian P, De Ugarte DA, Huang JI, Mizuno H, Alfonso ZC, Fraser JK, Benhaim P, Hedrick MH. Human adipose tissue is a source of multipotent stem cells. Mol Biol Cell. 2002;13:4279–95.

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Keele University, ISTM at RJAH Orthopaedic Hospital, Oswestry, Shropshire, UK

    Alasdair G. Kay & Oksana Kehoe

  2. University of Bristol, Faculty of Medicine and Dentistry, Bristol, UK

    Jim Middleton

Authors
  1. Alasdair G. Kay
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jim Middleton
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Oksana Kehoe
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Oksana Kehoe .

Editor information

Editors and Affiliations

  1. Laboratory of Stem Cell Research and Application, University of Science Vietnam National University, Ho Chi Minh City, Vietnam

    Phuc Van Pham

Rights and permissions

Reprints and permissions

Copyright information

© 2016 Springer International Publishing Switzerland

About this chapter

Cite this chapter

Kay, A.G., Middleton, J., Kehoe, O. (2016). Mesenchymal Stem Cell Therapy in Rheumatoid Arthritis. In: Pham, P. (eds) Bone and Cartilage Regeneration. Stem Cells in Clinical Applications. Springer, Cham. https://doi.org/10.1007/978-3-319-40144-7_8

Download citation

Publish with us

Policies and ethics

Search

Navigation