Rheumatoid Arthritis and Stem Cells

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Mesenchymal stem cells, autoimmunity and rheumatoid arthritis

QJM. 2014 Mar 5;
Authors: El-Jawhari JJ, El-Sherbiny YM, Jones EA, McGonagle D

Abstract
The vast majority of literature pertaining to mesenchymal stem cells (MSC) immunomodulation has focussed on bone marrow-derived MSC that are systemically infused to alleviate inflammatory conditions. Rheumatoid arthritis (RA) is the commonest autoimmune joint disease that has witnessed significant therapeutic advances in the past decade, but remains stubbornly difficult to treat in a subset of cases. Pre-clinical research has demonstrated that bone marrow, adipose, synovial and umbilical cord-derived MSC all suppress the functions of different immune cells thus raising the possibility of new therapies for autoimmune diseases including RA. Indeed, preliminary evidence for MSC efficacy has been reported in some cases of RA and systemic lupus erythromatosis. The potential use of bone marrow-MSC (BM-MSC) for RA therapy is emerging but the use of synovial MSC (S-MSC) to suppress the exaggerated immune response within the inflamed joints remains rudimentary. Synovial fibroblasts that are likely derived from S-MSCs, also give rise to a cell-cultured progeny termed fibroblast-like synoviocytes (FLS), which are key players in the perpetuation of joint inflammation and destruction. A better understanding of the link between these cells and their biology could be a key to developing novel MSC-based strategies for therapy. The review briefly focuses on BM-MSC and gives particular attention to joint niche synovial MSC and FLS with respect to immunoregulatory potential therapy roles.

PMID: 24518000 [PubMed - as supplied by publisher]

Interleukin-17A- or tumor necrosis factor α-mediated increase in proliferation of T cells cocultured with synovium-derived mesenchymal stem cells in rheumatoid arthritis

Arthritis Res Ther. 2013;15(5):R169
Authors: Zhang Z, Ding Y, Li W, Song B, Yang R

Abstract
INTRODUCTION: Mesenchymal stem cells (MSCs) represent promising applications in rheumatoid arthritis (RA). However, the inflammatory niche in the RA synovium could adversely affect MSC function. This study was designed to investigate biologic and immunologic properties of synovium-derived MSCs (SMSCs) in RA, with particular focus on whether cytokines can mediate increase of proliferation of T cells cocultured with SMSCs in RA.

METHODS: Compared with SMSCs from eight healthy donors (HDs), SMSCs from 22 patients with RA (RAp) were evaluated. The methyl thiazolyl tetrazolium (MTT) assay was used to assess cell-population doubling and viability. Multipotentiality of SMSCs was examined by using appropriate culture conditions. Flow cytometry was used to investigate the marker phenotype of SMSCs. Immunomodulation potential of SMSCs was examined by mixed peripheral blood mononuclear cells (PBMCs) reactions, and then by PBMCs or synovial T cells with or without the addition of inflammatory cytokines (interleukin-17A (IL-17A), tumor necrosis factor-α (TNF-α), and interferon-γ (IFN-γ)) after stimulation with phytohemagglutinin (PHA), respectively.

RESULTS: SMSCs from RA patients (RA-SMSCs) showed normal population doubling, cell viability, multiple differentiation characteristics, and surface markers. In either mixed PBMC reactions or PBMC proliferation stimulated with PHA, RA-SMSCs showed normal immunomodulation function compared with SMSCs from healthy donors (HD-SMSCs). However, the increase in proliferation of T cells was observed when IL-17A and TNF-α were added alone or in combination.

CONCLUSIONS: Our data suggest that the inflammatory niche, especially these cytokines, may increase the proliferation of T cells cocultured with SMSCs in RA.

PMID: 24286220 [PubMed - in process]

Human umbilical cord mesenchymal stem cell therapy for patients with active rheumatoid arthritis: safety and efficacy

Stem Cells Dev. 2013 Dec 15;22(24):3192-202
Authors: Wang L, Wang L, Cong X, Liu G, Zhou J, Bai B, Li Y, Bai W, Li M, Ji H, Zhu D, Wu M, Liu Y

Abstract
This study was designed to assess the safety and efficacy of human umbilical cord mesenchymal stem cells (UC-MSCs) in the treatment of rheumatoid arthritis (RA). In this ongoing cohort, 172 patients with active RA who had inadequate responses to traditional medication were enrolled. Patients were divided into two groups for different treatment: disease-modifying anti-rheumatic drugs (DMARDs) plus medium without UC-MSCs, or DMARDs plus UC-MSCs group (4×10(7) cells per time) via intravenous injection. Adverse events and the clinical information were recorded. Tests for serological markers to assess safety and disease activity were conducted. Serum levels of inflammatory chemokines/cytokines were measured, and lymphocyte subsets in peripheral blood were analyzed. No serious adverse effects were observed during or after infusion. The serum levels of tumor necrosis factor-alpha and interleukin-6 decreased after the first UC-MSCs treatment (P<0.05). The percentage of CD4(+)CD25(+)Foxp3(+) regulatory T cells of peripheral blood was increased (P<0.05). The treatment induced a significant remission of disease according to the American College of Rheumatology improvement criteria, the 28-joint disease activity score, and the Health Assessment Questionnaire. The therapeutic effects maintained for 3-6 months without continuous administration, correlating with the increased percentage of regulatory T cells of peripheral blood. Repeated infusion after this period can enhance the therapeutic efficacy. In comparison, there were no such benefits observed in control group of DMARDS plus medium without UC-MSCs. Thus, our data indicate that treatment with DMARDs plus UC-MSCs may provide safe, significant, and persistent clinical benefits for patients with active RA.

PMID: 23941289 [PubMed - in process]

Regulation of osteoclastogenesis by human mesenchymal stem cells leading to application of a novel treatment for rheumatoid arthritis

J UOEH. 2013 Mar 1;35(1):33-7
Authors: Oshita K, Yamaoka K, Tanaka Y

Abstract
Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease characterized by synovitis and bone destruction leading to irreversible joint deformity. The development of a novel treatment for RA aiming at joint repair is necessary. Recently, mesenchymal stem cells (MSCs) have been widely studied as a new therapeutic tool for the treatment of RA, due to their multipotency and also their immunosuppressive properties. We show here that MSCs inhibit osteoclast differentiation depending on the constitutive production of osteoprotegerin, a decoy receptor of receptor activator of nuclear factor kappa-B ligand (RANKL). Our results further indicate that MSCs are useful in RA treatment by preventing the progression of bone damage by inhibiting osteoclast differentiation. In addition, MSCs are likely to play important roles in bone metabolism and maintenance of joint formation. In conclusion, MSC is a promising tool for both anti-inflammation and bone repair for RA patients.

PMID: 23475022 [PubMed - indexed for MEDLINE]

Successful reduced-intensity umbilical cord blood transplant for fulminant hemophagocytic syndrome in an adult with pre-existing rheumatoid arthritis and autoimmune hemolytic anemia

Leuk Lymphoma. 2012 Nov;53(11):2307-9
Authors: Itamura H, Fukushima N, Kondo S, Urata C, Tanaka-Yoshimura M, Yokoo M, Ide M, Hisatomi T, Kubota Y, Sueoka E, Ichinohe T, Kimura S

PMID: 22452588 [PubMed - indexed for MEDLINE]

Rheumatoid arthritis: umbilical cord stem cells–the birth of a new treatment for RA?

Nat Rev Rheumatol. 2011 Feb;7(2):69
Authors: Price S

PMID: 21374898 [PubMed]

Synovial fluid of patients with rheumatoid arthritis induces alpha-smooth muscle actin in human adipose tissue-derived mesenchymal stem cells through a TGF-beta1-dependent mechanism

Exp Mol Med. 2010 Aug 31;42(8):565-73
Authors: Song HY, Kim MY, Kim KH, Lee IH, Shin SH, Lee JS, Kim JH

Abstract
Rheumatoid arthritis (RA) is a chronic, inflammatory autoimmune disorder that causes the immune system to attack the joints. Transforming growth factor-beta1 (TGF-beta1) is a secreted protein that promotes differentiation of synovial fibroblasts to alpha-smooth muscle actin (alpha-SMA)-positive myofibroblasts to repair the damaged joints. Synovial fluid from patients with RA (RA-SF) induced expression of alpha-SMA in human adipose tissue-derived mesenchymal stem cells (hASCs). RA-SF-induced alpha-SMA expression was abrogated by immunodepletion of TGF-beta1 from RA-SF with anti-TGF-beta1 antibody. Furthermore, pretreatment of hASCs with the TGF-beta type I receptor inhibitor SB431542 or lentiviral small hairpin RNA-mediated silencing of TGF-beta type I receptor expression in hASCs blocked RA-SF-induced alpha-SMA expression. Small interfering RNA-mediated silencing of Smad2 or adenoviral overexpression of Smad7 (an inhibitory Smad isoform) completely inhibited RA-SF-stimulated alpha-SMA expression. These results suggest that TGF-beta1 plays a pivotal role in RA-SF-induced differentiation of hASCs to alpha-SMA-positive cells.

PMID: 20628268 [PubMed - indexed for MEDLINE]

Lysophosphatidic acid mediates migration of human mesenchymal stem cells stimulated by synovial fluid of patients with rheumatoid arthritis

Biochim Biophys Acta. 2010 Jan;1801(1):23-30
Authors: Song HY, Lee MJ, Kim MY, Kim KH, Lee IH, Shin SH, Lee JS, Kim JH

Abstract
Migration of mesenchymal stem cells plays a key role in regeneration of injured tissues. Rheumatoid arthritis (RA) is a chronic inflammatory disease and synovial fluid (SF) reportedly contains a variety of chemotactic factors. This study was undertaken to investigate the role of SF in migration of human bone marrow-derived mesenchymal stem cells (hBMSCs) and the molecular mechanism of SF-induced cell migration. SF from RA patients greatly stimulated migration of hBMSCs and the SF-induced migration was completely abrogated by pretreatment of the cells with the lysophosphatidic acid (LPA) receptor antagonist Ki16425 and by small interfering RNA- or lentiviral small hairpin RNA-mediated silencing of endogenous LPA(1)/Edg2. Moreover, SF from RA patients contains higher concentrations of LPA and an LPA-producing enzyme autotoxin than normal SF. In addition, SF from RA patients increased the intracellular concentration of calcium through a Ki16425-sensitive mechanism and pretreatment of the cells with the calmodulin inhibitor W7 or calmodulin-dependent protein kinase II inhibitor KN93 abrogated the SF-induced cell migration. These results suggest that LPA-LPA(1) plays a key role in the migration of hBMSCs induced by SF from RA patients through LPA(1)-dependent activation of calmodulin-dependent protein kinase II.

PMID: 19733258 [PubMed - indexed for MEDLINE]

Identification of mesenchymal stem cells derived from rheumatoid arthritis synovial fluid and their regulatory effect on osteoblast formation

Zhongguo Shi Yan Xue Ye Xue Za Zhi. 2009 Aug;17(4):977-80
Authors: Zhu H, Jiang XX, Wu Y, Liu YL, Li XS, Zhang Y, Mao N

Abstract
This study was purposed to investigate the influence of inflammatory microenvironment on mesenchymal stem cells (MSCs) and regulatory effect of MSCs on osteoblast formation. The MSCs were isolated from synovial fluid of patients with rheumatoid arthritis (RASF-MSCs) and were cultured, the immunotypes of RASF-MSCs were detected by flow cytometry, the ability to differentiate RASF-MSCs into osteoblasts and adipocytes was determined by means of osteogenic and adipogenic induction, the regulatory effect of RASF-MSCs on osteoblast formation was assayed by co-culturing RASF-MSCs whth CD14(+) monocytes and in situ tartrate-resistant acid phosphatase staining. The results showed that RASF-MSCs highly expressed CD105, CD73, CD29, CD44, CD166 and HLA-ABC. Meanwhile, they lowly expressed CD34, CD45, CD31, HLA-DR, CD80 and CD86. However, RASF-MSCs decreased multi-differentiation capability as compared with BM-MSCs. More interestingly, RASF-MSC significantly promoted osteoclasts formation (p < 0.05) when co-cultured with monocytes. It is concluded that MSCs from rheumatoid arthritis synovial fluid exert typical MSC phenotypes but displayed decline of multi-differentiation capability. RASF-MSCs especially show promoting effect on osteoclastogenesis. The findings of this study may contribute to the understanding biological behavior of MSCs in pathological microenvironment.

PMID: 19698242 [PubMed - indexed for MEDLINE]

Human adipose-derived mesenchymal stem cells reduce inflammatory and T cell responses and induce regulatory T cells in vitro in rheumatoid arthritis

Ann Rheum Dis. 2010 Jan;69(1):241-8
Authors: Gonzalez-Rey E, Gonzalez MA, Varela N, O’Valle F, Hernandez-Cortes P, Rico L, Büscher D, Delgado M

Abstract
OBJECTIVES: Adult mesenchymal stem cells were recently found to suppress effector T cell and inflammatory responses and have emerged as attractive therapeutic candidates for immune disorders. In rheumatoid arthritis (RA), a loss in the immunological self-tolerance causes the activation of autoreactive T cells against joint components and subsequent chronic inflammation. The aim of this study is to characterise the immunosuppressive activity of human adipose-derived mesenchymal stem cells (hASCs) on collagen-reactive T cells from patients with RA.

METHODS: The effects of hASCs on collagen-reactive RA human T cell proliferation and cytokine production were investigated, as well as effects on the production of inflammatory mediators by monocytes and fibroblast-like synoviocytes from patients with RA.

RESULTS: hASCs suppressed the antigen-specific response of T cells from patients with RA. hASCs inhibited the proliferative response and the production of inflammatory cytokines by collagen-activated CD4 and CD8 T cells. In contrast, the numbers of IL10-producing T cells and monocytes were significantly augmented upon hASC treatment. The suppressive activity of hASCs was cell-to-cell contact dependent and independent. hASCs also stimulated the generation of FoxP3 protein-expressing CD4(+)CD25(+) regulatory T cells, with the capacity to suppress collagen-specific T cell responses. Finally, hASCs downregulated the inflammatory response and the production of matrix-degrading enzymes by synovial cells isolated from patients with RA.

CONCLUSIONS: The present work identifies hASCs as key regulators of immune tolerance, with the capacity to suppress T cell and inflammatory responses and to induce the generation/activation of antigen-specific regulatory T cells.

PMID: 19124525 [PubMed - indexed for MEDLINE]

Functional, molecular and proteomic characterisation of bone marrow mesenchymal stem cells in rheumatoid arthritis

Ann Rheum Dis. 2008 Jun;67(6):741-9
Authors: Kastrinaki MC, Sidiropoulos P, Roche S, Ringe J, Lehmann S, Kritikos H, Vlahava VM, Delorme B, Eliopoulos GD, Jorgensen C, Charbord P, Häupl T, Boumpas DT, Papadaki HA

Abstract
OBJECTIVE: Bone marrow (BM) mesenchymal stem cells (MSCs) are being considered as potential therapeutic agents in various inflammatory autoimmune diseases for their tissue-repair and anti-inflammatory tissue-protective properties. This study investigates the reserves and function, the molecular and proteomic profile and the differentiation potential of BM MSCs in patients with active rheumatoid arthritis (RA).

METHODS: We evaluated the frequency of MSCs in the BM mononuclear cell fraction using a limiting dilution assay, the proliferative/clonogenic potential and the capacity of cells to differentiate towards the osteogenic/chondrogenic/adipogenic lineages using appropriate culture conditions. We also assessed the molecular and proteomic characteristics in terms of inflammatory cytokine gene and protein expression, the relative telomere length and the survival characteristics of BM MSCs.

RESULTS: MSCs from patients with RA (n = 26) and age- and sex-matched healthy individuals (n = 21) were similar in frequency, differentiation potential, survival, immunophenotypic characteristics, and protein profile. Patient MSCs, however, had impaired clonogenic and proliferative potential in association with premature telomere length loss. Transcriptome analysis revealed differential expression of genes related to cell adhesion processes and cell cycle progression beyond the G1 phase. Previous treatment with methotrexate, corticosteroids, anti-cytokine and biological agents or other disease-modifying anti-inflammatory drugs did not correlate with the clonogenic and proliferative impairment of BM MSCs.

CONCLUSION: In spite of some restrictions related to the impaired clonogenic and proliferative potential, our findings support the use of autologous BM MSCs in RA and may have important implications for the ongoing efforts to repair tissue injury commonly seen in the course of the disease.

PMID: 17921184 [PubMed - indexed for MEDLINE]

Mesenchymal stem cells and rheumatoid arthritis

Joint Bone Spine. 2003 Dec;70(6):483-5
Authors: Jorgensen C, Djouad F, Fritz V, Apparailly F, Plence P, Noël D

PMID: 14667559 [PubMed - indexed for MEDLINE]