Abstract
To compare human adipose tissue mesenchymal stem cells (AT-MSCs) and etanercept as immunomodulatory agents for collagen-induced arthritis (CIA). CIA was induced by rats’ immunization with collagen type II (CII) in complete Freund’s adjuvant in days 0 and 7. Before the onset of CIA, prevention group received five doses of AT-MSCS intraperitoneally. After establishment of arthritis, rats received either five doses of AT-MSCs or phosphate-buffered saline (PBS) intraperitoneally or six doses of etanercept subcutaneously. Clinical and histopathological evaluation were performed in all groups; serum levels of tumor necrosis factor-α (TNF-α), interleukin-10 (IL-10), and anti-collagen II were assessed by enzyme-linked immunosorbent assay (ELISA). A total percent of autoreactive T and regulatory T (Treg) cells were quantified using spleen immune histochemical analysis. AT-MSCs were able to delay the onset of CIA, suppress the ongoing clinical and histopathological signs, decrease serum levels of TNF-α and anti-collagen type II, and downregulate the autoreactive T cells as etanercept. AT-MSCs were more potent in Treg cells upregulation, producing high serum levels of IL10. AT-MSCs might have a therapeutic effect in CIA via their potency in immune cell education, representing an effective new promising approach in rheumatoid arthritis in human.
Similar content being viewed by others
Abbreviations
- AT-MSCs:
-
Adipose tissue mesenchymal stem cells
- BM-MSCs:
-
Bone marrow–derived MSCs
- CIA:
-
Collagen-induced arthritis
- CII:
-
Collagen type II
- DMARDs:
-
Disease-modifying anti-rheumatic drugs
- DMEM:
-
Dulbecco’s Modified Eagle’s Medium
- ELISA:
-
Enzyme-linked immunosorbent assay
- FACS:
-
Fluorescence-activated cell sorting
- FBS:
-
Fetal bovine serum
- FOXP3:
-
Forkhead box P3
- IL-10:
-
Interleukin-10
- mAb:
-
Monoclonal antibodies
- MERC:
-
Medical Experimental Research Center
- MSCs:
-
Mesenchymal stem cells
- PBS:
-
Phosphate-buffered saline
- RA:
-
Rheumatoid arthritis
- TNF-α:
-
Tumor necrosis factor-α
- Treg:
-
Regulatory T cells
References
Firestein GS. Evolving concepts of rheumatoid arthritis. Nature. 2003;423:356–61.
Bluml S, Scheinecker C, Smolen JS, Redlich K. Targeting TNF receptors in rheumatoid arthritis. Int Immunol. 2012;24:275–81.
McInnes IB, Buckley CD, Isaacs JD. Cytokines in rheumatoid arthritis: shaping the immunological landscape. Nat Rev Rheumatol. 2016;12:63–6.
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.
Gimble JM, Bunnell BA, Frazier T, Rowan B, Shah F, Thomas-Porch C, et al. Adipose-derived stromal/stem cells: a primer. Organogenesis. 2013;9:3–10.
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(6):1421–32.
Takano T, Li YJ, Kukita A, Yamaza T, Ayukawa Y, Moriyama K, et al. Mesenchymal stem cells markedly suppress inflammatory bone destruction in rats with adjuvant-induced arthritis. Lab Investig. 2014;94(3):286–96.
Brand DD, Latham KA, Rosloniec EF. Collagen-induced arthritis. Nat Protoc. 2007;2(5):1269–75.
Fouda AMM, Berika MY. Evaluation of the effect of hydroalcoholic extract of Zingiber officinale rhizomes in rat collagen-induced arthritis. Basic Clin Pharmacol Toxicol. 2009;104:262–71.
Zhou B, Yuan J, Zhou Y, Ghawji M Jr, Deng YP, Lee AJ, et al. Administering human adipose-derived mesenchymal stem cells to prevent and treat experimental arthritis. Clin Iimmunol. 2011;141(3):328–37.
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 The. 2010;12(6):R210.
Zuk PA, Zuh M, Mizuno H, Huang J, Futrell JW, Katz AJ, et al. Multilineage cells from human adipose tissue: implications for cell-based therapies. Tissue Eng. 2001;7:211–28.
Tucker HA, Bunnell BA. Characterization of human adipose-derived stem cells using flow cytometry. Methods Mol Biol. 2011;702:121–31.
Lotfy A, El-Sherbiny YM, Cuthbert R, Jones E, Badawy A. Comparative study of biological characteristics of mesenchymal stem cells isolated from mouse bone marrow and peripheral blood. Biomed Rep. 2019;11(4):165–70.
Gonza’lez MA, Gonza’lez-Rey E, Rico L, et al. Treatment of experimental arthritis by inducing immune tolerance with human adipose-derived mesenchymal stem cells. Arthritis Rheum. 2009;60(4):1006–19.
Hodgetts S, Radley H, Davies M, et al. Reduced necrosis of dystrophic muscle by depletion of host neutrophils, or blocking TNFa function with Etanercept in mdx mice. Neuromuscul Disord. 2006;16:591–602.
Setoguchi C, Tsuji F, Katsuta O, et al. Combined effects of bucillamine and etanercept on a rat type II collagen-induced arthritis model. Mod Rheumatol. 2010;20:381–8.
Waynforth HB, Flecknell PA. Methods of obtaining body fluids. In: Waynforth HB, Flecknell PA, editors. Techniques in the rat. London: Elsevier Academic Press; 1992. p. 68–99.
Tong T, Zhao W, Wu YQ, Chang Y, Wang QT, Zhang LL, et al. Chicken type II collagen induced immune balance of main subtype of helper T cells in mesenteric lymph node lymphocytes in rats with collagen-induced arthritis. Inflamm Res. 2010;59:369–77.
Dimitrakopoulos F, Papadak H, Antonacopoulou A, et al. Association of FOXP3 expression with non-small cell lung. Cancer Anticancer Res. 2011;31:1677–84.
Zampeli E, Vlachoyiannopoulos PG, Tzioufas AG. Treatment of rheumatoid arthritis: unraveling the conundrum. J.Autoimmun. 2015;65:1–18.
El-Jawhari JJ, El-Sherbiny YM, Jones EA, et al. Mesenchymal stem cells, autoimmunity and rheumatoid arthritis. JM. 2014;107(7):505–14.
Sullivan C, Barry F, Ritter T, et al. Allogeneic murine mesenchymal stem cells: migration to inflamed joints in vivo and amelioration of collagen induced arthritis when transduced to express CTLA4Ig. Stem Cells Dev. 2013;22:3203–13.
Gonzalo-Gil E, Pérez-Lorenzo MJ, Galindo M, Díaz de la Guardia R, López-Millán B, Bueno C, et al. Human embryonic stem cell-derived mesenchymal stromal cells ameliorate collagen-induced arthritis by inducing host-derived indoleamine 2, 3 dioxygenase. Arthritis Res Ther. 2016;18:77.
Bernardo ME, Fibbe WE. Mesenchymal stromal cells: sensors and switchers of inflammation. Cell Stem Cell. 2013;13(4):392–402.
Yan L, Zheng D, Xu R-H. Critical role of tumor necrosis factor signaling in mesenchymal stem cell-based therapy for autoimmune and inflammatory diseases. Front Immunol. 2018;9:1658.
Bouffi C, Bony C, Courties G, et al. IL-6-dependent PGE2 secretion by mesenchymal stem cells inhibits local inflammation in experimental arthritis. PLoS One. 2010;5:e14247.
Lee WJ, Hah YS, Ock SA, Lee JH, Jeon RH, Park JS, et al. 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;333:273–88.
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.
Gu Y, Shi S. Transplantation of gingiva-derived mesenchymal stem cells ameliorates collagen-induced arthritis. Arthritis Res Ther. 2016;18(1):262.
Sun Y, Kong W, Huang S, et al. Comparable therapeutic potential of umbilical cord mesenchymal stem cells in collagen-induced arthritis to TNF inhibitor or anti-CD20 treatment. Clin Exp Rheumatol. 2017;35:288–95.
Mancheño-Corvo P, Lopez-Santalla M, Menta R, et al. Intralymphatic administration of adipose mesenchymal stem cells reduces the severity of collagen- induced experimental arthritis. Front Immunol. 2017;8:462.
Lee K, Park N, Jung H, Rim YA, Nam Y, Lee J, et al. Mesenchymal stem cells ameliorate experimental arthritis via expression of interleukin-1 receptor antagonist. PLoS One. 2018;13(2):e0193086.
Abdelmawgoud H, Saleh A. Anti-inflammatory and antioxidant effects of mesenchymal and hematopoietic stem cells in a rheumatoid arthritis rat model. Adv Clin Exp Med. 2018;27(7):873–80.
Park N, Rim YA, Jung H, et al. Etanercept-synthesising mesenchymal stem cells efficiently ameliorate collagen-induced arthritis. Sci Rep. 2017;7:39593.
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.
Lopez-Santalla M, No-Corvo PM, Menta R, et al. Human adipose-derived mesenchymal stem cells modulate experimental autoimmune arthritis by modifying early adaptive T cell responses. Stem Cells. 2015;33:3493–503.
Lim JY, Im KI, Lee ES, Kim N, Nam YS, Jeon YW, et al. Enhanced immunoregulation of mesenchymal stem cells by IL-10-producing type 1 regulatory T cells in collagen-induced arthritis. Sci Rep. 2016;6:26851.
Choi EW, Shin IS, Song JW, Lee M, Yun TW, Yang J, et al. Effects of transplantation of CTLA4Ig-overexpressing adipose tissue-derived mesenchymal stem cells in mice with sustained severe rheumatoid arthritis. Cell Transplant. 2016;25:243–59.
Nam Y, Jung SM, Rim YA, Jung H, Lee K, Park N, et al. Intraperitoneal infusion of mesenchymal stem cell attenuates severity of collagen antibody induced arthritis. PLoS One. 2018;13(6):e0198740.
Ellsworth JL, Hamacher N, Harder B, et al. Recombinant soluble human FcgammaR1A (CD64A) reduces inflammation in murine collagen-induced arthritis. J Immunol. 2009;182(11):7272–9.
Shu J, Pan L, Huang X, et al. Transplantation of human amnion mesenchymal cells attenuates the disease development in rats with collagen-induced arthritis. Clin Exp Rheumatol. 2015;33:484–90.
Garimella MG, Kour S, Piprode V, Mittal M, Kumar A, Rani L, et al. Adipose-derived mesenchymal stem cells prevent systemic bone loss in collagen-induced arthritis. J Immunol. 2015;195(11):5136–48.
Franceschetti T, De Bari C. The potential role of adult stem cells in the management of the rheumatic diseases. Ther Adv Musculoskelet Dis. 2017;9(7):165–79.
Yan X, Cen Y, Wang Q. Mesenchymal stem cells alleviate experimental rheumatoid arthritis through microRNA-regulated IκB expression. Sci Rep. 2016;6:28915.
Ansboro S, Roelofs AJ, de Bari C. Mesenchymal stem cells for management of rheumatoid arthritis: immune modulation, repair or both? Curr Opin Rheumatol. 2017;29(2):201–7.
Zhang L, Wang XY, Zhou PJ, He Z, Yan HZ, Xu DD, et al. Use of immune modulation by human adipose-derived mesenchymal stem cells to treat experimental arthritis in mice. Am J Transl Res. 2017;9:2595–607.
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 alpha in collagen-induced arthritis. Arthritis Rheum. 2005;52:1595–603.
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.
Wu CC, Wu TC, Liu FL, Sytwu HK, Chang DM. TNF-alpha inhibitor reverse the effects of human umbilical cord-derived stem cells on experimental arthritis by increasing immunosuppression. Cell Immunol. 2012;273:30–40.
Papadopoulou A, Yiangou M, Athanasiou E, et al. Mesenchymal stem cells are conditionally therapeutic in preclinical models of rheumatoid arthritis. Ann Rheum Dis. 2012;71(10):1733–40.
Karamini A, Bakopoulou A, Andreadis D, Gkiouras K, Kritis A. Therapeutic potential of mesenchymal stromal stem cells in rheumatoid arthritis: a systematic review of in vivo studies. Stem Cell Rev Rep. 2020;16:276–87. https://doi.org/10.1007/s12015-020-09954-z.
Acknowledgments
The authors would like to thank all members of MERC and Medical Biochemistry Department at Mansoura University for their helpful guidance and support.
Funding
This work was totally funded by authors.
Availability of data and materialsThe data used to support the findings of this study are available from the corresponding author upon request.
Author information
Authors and Affiliations
Contributions
SHE, MA, and MAM conceived, designed, supervised, and commented on all the drafts of this paper. HEG, MAm, HAA, SF, and AL conducted the overall experiments and participated in the clinical data collection, analysis, laboratory, and histopathological investigations. HEG and AL contributed to the data interpretation and helped in manuscript completion. All authors read and approved the final manuscript.
Corresponding author
Ethics declarations
Conflict of interest
The authors declare that they have no competing interests.
Ethics approval and consent to participate
The study was authorized by animal ethics committee of Mansoura University.
Additional information
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Highlights
• AT-MSCs could delay and suppress both clinical and histopathological features of rat CIA.
• AT-MSCs were proven to be an immunomodulatory agent that reestablish immunologic tolerance in CIA.
• AT-MSCs may require sufficient time for migration to lymphoid organs to target the immune cells.
Electronic supplementary material
ESM 1
(DOCX 4809 kb)
Rights and permissions
About this article
Cite this article
El-Gendy, H., Hawass, S.ED., Awad, M. et al. Comparative study between human mesenchymal stem cells and etanercept as immunomodulatory agents in rat model of rheumatoid arthritis. Immunol Res 68, 255–268 (2020). https://doi.org/10.1007/s12026-020-09132-w
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12026-020-09132-w