International Journal of Stem Cells

Korean Society for Stem Cell Research (한국줄기세포학회)
권호 표지
DOI QR코드

DOI QR Code

Xenogeneic Humoral Immune Responses to Human Mesenchymal Stem Cells in Mice

  • Jun-Man Hong (Department of Anatomy and Cell Biology, Seoul National University College of Medicine) ;
  • Jin-Hee Kim (Medical Research Institute, Seoul National University College of Medicine) ;
  • Gwang-Hoon Kim (Department of Anatomy and Cell Biology, Seoul National University College of Medicine) ;
  • Hyun-Mu Shin (Department of Biomedical Sciences, Seoul National University College of Medicine) ;
  • Young-il Hwang (Department of Anatomy and Cell Biology, Seoul National University College of Medicine)
  • Received : 2021.06.24
  • Accepted : 2021.10.16
  • Published : 2022.08.30
Download PDF
⟨ Previous Next ⟩

Abstract

Background and Objectives: Many preclinical studies have been conducted using animal disease models to determine the effectiveness of human mesenchymal stem cells (hMSCs) for treating immune and inflammatory diseases based on the belief that hMSCs are not immunogenic across species. However, several researchers have suggested xenogeneic immune responses to hMSCs in animals, still without detailed features. This study aimed to investigate a xenogeneic humoral immune response to hMSCs in mice in detail. Methods and Results: Balb/c mice were intraperitoneally injected with adipose tissue-derived or Wharton's jelly-derived hMSCs. Sera from these mice were titrated for each isotype. To confirm specificity of the antibodies, hMSCs were stained with the sera and subjected to a flow cytometic analysis. Spleens were immunostained for proliferating cell nuclear antigen to verify the germinal center formation. Additionally, splenocytes were subjected to a flow cytometric analysis for surface markers including GL-7, B220, CD4, CD8, CD44, and CD62L. Similar experiments were repeated in C57BL/6 mice. The results showed increased IgG1 and IgG2a titers in the sera from Balb/c mice injected with hMSCs, and the titers were much higher in the secondary sera than in the primary sera. These antibodies were specifically stained the hMSCs. Germinal centers were observed in the spleen, and flow cytometric analysis of the splenocytes showed higher frequencies of centroblasts (B220+ GL7+) and memory T cells (CD62L+ CD44+) both in CD4+ and CD8+ subsets. Similar results were obtained for C57BL/6 mice. Conclusions: hMSCs induced a humoral immune response in mice, with characters of T cell-dependent immunity.

Keywords

Acknowledgement

This research was supported exclusively by the Bio & Medical Technology Development Program of the National Research Foundation (NRF) funded by the Ministry of Science, ICT & Future Planning (NRF-2015M3A9E6028677). No any other financial sources support this study.

References

  1. To K, Zhang B, Romain K, Mak C, Khan W. Synovium-derived mesenchymal stem cell transplantation in cartilage regeneration: a PRISMA review of in vivo studies. Front Bioeng Biotechnol 2019;7:314 
  2. Ansari AS, Yazid MD, Sainik NQAV, Razali RA, Saim AB, Idrus RBH. Osteogenic induction of Wharton's jelly-derived mesenchymal stem cell for bone regeneration: a systematic review. Stem Cells Int 2018;2018:2406462 
  3. Hu C, Zhao L, Li L. Current understanding of adipose-derived mesenchymal stem cell-based therapies in liver diseases. Stem Cell Res Ther 2019;10:199 
  4. Cofano F, Boido M, Monticelli M, Zenga F, Ducati A, Vercelli A, Garbossa D. Mesenchymal stem cells for spinal cord injury: current options, limitations, and future of cell therapy. Int J Mol Sci 2019;20:2698 
  5. Le Blanc K, Rasmusson I, Sundberg B, Gotherstrom C, Hassan M, Uzunel M, Ringden O. Treatment of severe acute graft-versus-host disease with third party haploidentical mesenchymal stem cells. Lancet 2004;363:1439-1441 
  6. Alvaro-Gracia JM, Jover JA, Garcia-Vicuna R, Carreno L, Alonso A, Marsal S, Blanco F, Martinez-Taboada VM, Taylor P, Martin-Martin C, DelaRosa O, Tagarro I, DiazGonzalez F. Intravenous administration of expanded allogeneic adipose-derived mesenchymal stem cells in refractory rheumatoid arthritis (Cx611): results of a multicentre, dose escalation, randomised, single-blind, placebo-controlled phase Ib/IIa clinical trial. Ann Rheum Dis 2017;76:196-202 
  7. Zhang J, Lv S, Liu X, Song B, Shi L. Umbilical cord mesenchymal stem cell treatment for Crohn's disease: a randomized controlled clinical trial. Gut Liver 2018;12:73-78 
  8. Schepers K, Fibbe WE. Unraveling mechanisms of mesenchymal stromal cell-mediated immunomodulation through patient monitoring and product characterization. Ann N Y Acad Sci 2016;1370:15-23 
  9. Prockop DJ, Oh JY, Lee RH. Data against a common assumption: xenogeneic mouse models can be used to assay suppression of immunity by human MSCs. Mol Ther 2017;25:1748-1756 
  10. Buja LM, Vela D. Immunologic and inflammatory reactions to exogenous stem cells implications for experimental studies and clinical trials for myocardial repair. J Am Coll Cardiol 2010;56:1693-1700 
  11. Pigott JH, Ishihara A, Wellman ML, Russell DS, Bertone AL. Investigation of the immune response to autologous, allogeneic, and xenogeneic mesenchymal stem cells after intra-articular injection in horses. Vet Immunol Immunopathol 2013;156:99-106 
  12. Grinnemo KH, Mansson A, Dellgren G, Klingberg D, Wardell E, Drvota V, Tammik C, Holgersson J, Ringden O, Sylven C, Le Blanc K. Xenoreactivity and engraftment of human mesenchymal stem cells transplanted into infarcted rat myocardium. J Thorac Cardiovasc Surg 2004;127:1293-1300 
  13. Hwang JW, Lee NK, Yang JH, Son HJ, Bang SI, Chang JW, Na DL. A comparison of immune responses exerted following syngeneic, allogeneic, and xenogeneic transplantation of mesenchymal stem cells into the mouse brain. Int J Mol Sci 2020;21:3052 
  14. Choi EW, Lee HW, Shin IS, Park JH, Yun TW, Youn HY, Kim SJ. Comparative efficacies of long-term serial transplantation of syngeneic, allogeneic, xenogeneic, or CTLA4Ig-overproducing xenogeneic adipose tissue-derived mesenchymal stem cells on murine systemic lupus erythematosus. Cell Transplant 2016;25:1193-1206 
  15. Kim JH, Lee YT, Hong JM, Hwang YI. Suppression of in vitro murine T cell proliferation by human adipose tissue-derived mesenchymal stem cells is dependent mainly on cyclooxygenase-2 expression. Anat Cell Biol 2013;46:262-271 
  16. Jo CH, Kim OS, Park EY, Kim BJ, Lee JH, Kang SB, Lee JH, Han HS, Rhee SH, Yoon KS. Fetal mesenchymal stem cells derived from human umbilical cord sustain primitive characteristics during extensive expansion. Cell Tissue Res 2008;334:423-433 
  17. Kim JH, Lee YT, Oh K, Cho J, Lee DS, Hwang YI. Paradoxical effects of human adipose tissue-derived mesenchymal stem cells on progression of experimental arthritis in SKG mice. Cell Immunol 2014;292:94-101 
  18. Kim JH, Jo CH, Kim HR, Hwang YI. Comparison of immunological characteristics of mesenchymal stem cells from the periodontal ligament, umbilical cord, and adipose tissue. Stem Cells Int 2018;2018:8429042 
  19. Martin RM, Brady JL, Lew AM. The need for IgG2c specific antiserum when isotyping antibodies from C57BL/6 and NOD mice. J Immunol Methods 1998;212:187-192 
  20. Stevens TL, Bossie A, Sanders VM, Fernandez-Botran R, Coffman RL, Mosmann TR, Vitetta ES. Regulation of antibody isotype secretion by subsets of antigen-specific helper T cells. Nature 1988;334:255-258 
  21. Mills CD, Kincaid K, Alt JM, Heilman MJ, Hill AM. M-1/M-2 macrophages and the Th1/Th2 paradigm. J Immunol 2000;164:6166-6173 
  22. Jang IK, Jung HJ, Noh OK, Lee DH, Lee KC, Park JE. B7‑H1‑mediated immunosuppressive properties in human mesenchymal stem cells are mediated by STAT‑1 and not PI3K/Akt signaling. Mol Med Rep 2018;18:1842-1848 
  23. Wang Q, Yang Q, Wang Z, Tong H, Ma L, Zhang Y, Shan F, Meng Y, Yuan Z. Comparative analysis of human mesenchymal stem cells from fetal-bone marrow, adipose tissue, and Warton's jelly as sources of cell immunomodulatory therapy. Hum Vaccin Immunother 2016;12:85-96 
  24. Nauta AJ, Kruisselbrink AB, Lurvink E, Willemze R, Fibbe WE. Mesenchymal stem cells inhibit generation and function of both CD34＋-derived and monocyte-derived dendritic cells. J Immunol 2006;177:2080-2087 
  25. Chiesa S, Morbelli S, Morando S, Massollo M, Marini C, Bertoni A, Frassoni F, Bartolome ST, Sambuceti G, Traggiai E, Uccelli A. Mesenchymal stem cells impair in vivo T-cell priming by dendritic cells. Proc Natl Acad Sci U S A 2011;108:17384-17389 
  26. Corcione A, Benvenuto F, Ferretti E, Giunti D, Cappiello V, Cazzanti F, Risso M, Gualandi F, Mancardi GL, Pistoia V, Uccelli A. Human mesenchymal stem cells modulate B-cell functions. Blood 2006;107:367-372 
  27. Franquesa M, Mensah FK, Huizinga R, Strini T, Boon L, Lombardo E, DelaRosa O, Laman JD, Grinyo JM, Weimar W, Betjes MG, Baan CC, Hoogduijn MJ. Human adipose tissue-derived mesenchymal stem cells abrogate plasmablast formation and induce regulatory B cells independently of T helper cells. Stem Cells 2015;33:880-891 
  28. Kim DS, Jang IK, Lee MW, Ko YJ, Lee DH, Lee JW, Sung KW, Koo HH, Yoo KH. Enhanced immunosuppressive properties of human mesenchymal stem cells primed by interferon-γ. EBioMedicine 2018;28:261-273 
  29. Putra A, Ridwan FB, Putridewi AI, Kustiyah AR, Wirastuti K, Sadyah NAC, Rosdiana I, Munir D. The role of TNF-α induced MSCs on suppressive inflammation by increasing TGF-β and IL-10. Open Access Maced J Med Sci 2018;6:1779-1783 
  30. Wu TY, Liang YH, Wu JC, Wang HS. Interleukin-1β enhances umbilical cord mesenchymal stem cell adhesion ability on human umbilical vein endothelial cells via LFA-1/ICAM-1 interaction. Stem Cells Int 2019;2019:7267142 
  31. Meisel R, Zibert A, Laryea M, Gobel U, Daubener W, Dilloo D. Human bone marrow stromal cells inhibit allogeneic T-cell responses by indoleamine 2,3-dioxygenase-mediated tryptophan degradation. Blood 2004;103:4619-4621 
  32. Aggarwal S, Pittenger MF. Human mesenchymal stem cells modulate allogeneic immune cell responses. Blood 2005;105:1815-1822 
  33. Bauer TM, Jiga LP, Chuang JJ, Randazzo M, Opelz G, Terness P. Studying the immunosuppressive role of indoleamine 2,3-dioxygenase: tryptophan metabolites suppress rat allogeneic T-cell responses in vitro and in vivo. Transpl Int 2005;18:95-100 
  34. English K, Barry FP, Field-Corbett CP, Mahon BP. IFN-gamma and TNF-alpha differentially regulate immunomodulation by murine mesenchymal stem cells. Immunol Lett 2007;110:91-100 
  35. Massague J, Like B. Cellular receptors for type beta transforming growth factor. Ligand binding and affinity labeling in human and rodent cell lines. J Biol Chem 1985;260:2636-2645 
  36. Tan JC, Indelicato SR, Narula SK, Zavodny PJ, Chou CC. Characterization of interleukin-10 receptors on human and mouse cells. J Biol Chem 1993;268:21053-21059 
  37. Luk F, Carreras-Planella L, Korevaar SS, de Witte SFH, Borras FE, Betjes MGH, Baan CC, Hoogduijn MJ, Franquesa M. Inflammatory conditions dictate the effect of mesenchymal stem or stromal cells on B cell function. Front Immunol 2017;8:1042 
  38. Leibacher J, Henschler R. Biodistribution, migration and homing of systemically applied mesenchymal stem/stromal cells. Stem Cell Res Ther 2016;7:7 
  39. Braid LR, Wood CA, Wiese DM, Ford BN. Intramuscular administration potentiates extended dwell time of mesenchymal stromal cells compared to other routes. Cytotherapy 2018;20:232-244 
  40. Toupet K, Maumus M, Peyrafitte JA, Bourin P, van Lent PL, Ferreira R, Orsetti B, Pirot N, Casteilla L, Jorgensen C, Noel D. Long-term detection of human adipose-derived mesenchymal stem cells after intraarticular injection in SCID mice. Arthritis Rheum 2013;65:1786-1794