Immunomodulatory Effect of Human Umbilical Cord Blood-derived Mesenchymal Stem Cells on Activated T-lymphocyte
-
Parisa Lotfinejad
,
Karim Shamsasenjan
,
Behzad Baradaran
,
Elham Safarzadeh
,
Tohid Kazemi
,
Ali Akbar Movassaghpour
Abstract
Many studies have been performed about regenerative and immunomodulatory properties of mesenchymal stem cells (MSCs) and their application in different treatment approaches. The present study aimed to investigate the immunomodulatory effect of umbilical cord blood-derived mesenchymal stem cells (UCB-MSCs) on the gene expression profile of cytokines in stimulated T-lymphocytes.
For this purpose, MSCs were isolated from umbilical cord blood samples and cultured in Dulbecco's Modified Eagle Medium supplemented with 10% fetal bovine serum. The nature of MSCs was identified by flow cytometry analysis and differentiation to the adipocyte and osteocyte lineage. Moreover, to investigate the immunomodulatory effects of MSCs on T cells, a co-culture system was designed and expression levels of interleukin (IL)-2, IL-4, IL-6, IL-10, IL-13, interferon-gamma (IFN-γ), tumor necrosis factor-alpha (TNF-α), and transforming growth factor-beta (TGF-β) genes were measured; using the real-time polymerase chain reaction (RT-PCR) technique.
Our results demonstrated the ability of MSCs to differentiate into adipocyte and osteocyte lineages. Further investigation also displayed that although UCB-MSCs could significantly reduce the expression of pro-inflammatory cytokines like IL-2, IL-6, IFN-γ, and TNF-α in activated T-lymphocytes, they noticeably potentiated the expression levels of IL-4, IL-10, IL-13, and TGF-β in the co-culture setting.
In conclusion, UCB-MSCs have immunomodulatory effects on activated T-lymphocytes in favor of anti-inflammatory responses.
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3. Broxmeyer HE DG, Hangoc G, Cooper S, Bard J, English D, Arny M, Thomas L, Boyse EA. Human umbilical cord blood as a potential source of transplantable hematopoietic stem/progenitor cells. Proc Natl Acad Sci U S A. 1989;86(10):3828-32.
4. Dominici M LBK, Mueller I, Slaper-Cortenbach I, Marini F, Krause D, Deans R, Keating A, Prockop Dj, Horwitz E. Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy. 2006;8(4):315-7.
5. Swijnenburg RJ TM, Vogel H, Baker J, Kofidis T, Gunawan F, Lebl DR, Caffarelli AD, de Bruin JL, Fedoseyeva EV, Robbins RC. Embryonic stem cell immunogenicity increases upon differentiation after transplantation in to ischemic myocardium. Circulation. 2005;112(9):166-72.
6. In ‘t Anker PS SS, Kleijburg-van der Keur C, de Groot-Swings GM, Claas FH, Fibbe WE, Kanhai HH. Isolation of mesenchymal stem cells of fetal or maternal origin from human placenta. Stem Cells. 2004;22(4):1338-45.
7. Kim YJ BH. Immune regulatory cells in umbilical cord blood and their potential roles in transplantation tolerance. Crit Rev Oncol Hematol. 2011;79(2):112-26.
8. Wang M YY, Yang D, Luo F, Liang W, Guo S, Xu J. The immunomodulatory activity of human umbilical cord blood-derived mesenchymal stem cells in vitro. Immunology 2009;126(2):220-32.
9. Wang H-S HS-C, Peng S-T, et al. Mesenchymal stem cells in the Wharton’s jelly of the human umbilical cord. Stem Cells. 2004;22:1330-37.
10. Mazaheri T EA, H.KH. Mirzaei M. Introducing the immunomodulatory effects of mesenchymal stem cells in an experimental model of Behçet’s disease. Medical Hypotheses and Ideas 2012;6:23-7.
11. Nagamura-Inoue T HH. Umbilical cord-derived mesenchymal stem cells: Their advantages and potential clinical utility. World J Stem Cells. 2014;6(2):195-202.
12. A. Corcione FB, E. Ferretti et al. Human mesenchymal stem cells modulate B-cell functions. Blood. 2006;107(1):367-72.
13. A. Bartholomew CS, M. Siatskas et al. Mesenchymal stem cells suppress lymphocyte proliferation in vitro and prolong skin graft survival in vivo. Experimental Hematology. 2002;30(1):42-8.
14. C. Prevosto MZ, P. Canevali, M. R. Zocchi, and A. Poggi. Generation of CD4+ or CD8+ regulatory T cells upon mesenchymal stem cell-lymphocyte interaction. Haematologica. 2007;92(7):881-8.
15. Aggarwal S1 PM. Human mesenchymal stem cells modulate allogeneic immune cell responses. Blood. 2005;105(4):1815-22.
16. M. Di Nicola CC-S, M. Magni et al. Human bone marrow stromal cells suppress T-lymphocyte proliferation induced by cellular or nonspecific mitogenic stimuli. Blood. 2002;99(10):3838-43.
17. C. Campagnoli IAR, S. Kumar, P. R. Bennett, I. Bellantuono, and N. M. Fisk. Identification of mesenchymal stem/progenitor cells in human first-trimester fetal blood,liver, and bone marrow. Blood. 2001;98(8):2396-402.
18. Silva WA Jr CD, Panepucci RA, Proto-Siqueira R, Siufi JL, Zanette DL, Santos AR, Zago MA. The profile of gene expression of human marrow mesenchymal stem cells. Stem Cells. 2003;21(6):661-9.
19. Rezvany MR J-TM, Osterborg A, Kimby E, Wigzell H, Mellstedt H. Oligoclonal TCRBV Gene Usage in B-Cell Chronic Lymphocytic Leukemia: Major Perturbations Are Preferentially Seen Within the CD4 T-Cell Subset. Blood. 1999;94(3):1063-9.
20. Erices A CP, Minguell JJ. Mesenchymal progenitor cells in human umbilical cord blood. Br J Haematol. 2000;109(11):235-42.
21. Tipnis S VC, Majumdar AS. Immunosuppressive properties of human umbilical cord-derived mesenchymal stem cells: role of B7-H1 and IDO. Immunol Cell Biol. 2010 88(8):795-806.
22. Jin HJ NHY, Bae Y.K, Kim S.Y, Im I.R, Oh W, Yang Y.S, Choi S.J, Kim S.W. GD2 expression is closely associated with neuronal differentiation of human umbilical cord blood-derived mesenchymal stem cells. Cell Mol Life Sci. 2010;67(12):1845-58.
23. A J Engler SS, HL Sweeney, DE Discher. Matrix elasticity directs stem cell lineage specification. Cell Mol Life Sci. 2006;126(4): 677-89.
24. Divya MS RG, Divya TS, Rasheed VA, Santhoshkumar TR, Elizabeth KE, James J, Pillai RM. Umbilical cord blood-derived mesenchymal stem cells consist of a unique population of progenitors co-expressing mesenchymal stem cell and neuronal markers capable of instantaneous neuronal differentiation. Stem Cell Res Ther. 2012 3(6):57.
25. Zhang C CX, Zou ZM, Zhang X, Kong PY, Liang X, Gao L, Peng XG, Sun AH, Wang QY. Human umbilical cord blood-derived stromal cells suppress xenogeneic immune cell response in vitro. Croat Med J 2009;50:351-60.
26. Sakaguchi MM, Costantino CM,Hafler DA. FOXP3 + regulatory T cells in the human immune system. Immunol. 2010;10(4):490–500.
27. Fujimura T. YS, Taniguchi Y. et al. The induced regulatory T cell level, defined as the proportion of IL-10(+)Foxp3 (+) cells among CD25(+)CD4(+) leukocytes, is a potential therapeutic biomarker for sublingual immunotherapy: a preliminary report. Allergy Immunol. 2010;153(4):378–87.
28. Gonzalez MA G-RE, Rico L, Buscher D, Delgado M. Adiposederived mesenchymal stem cells alleviate experimental colitis by inhibiting inflammatory and autoimmune responses. Gastroenterology. 2009;136(4):978-89.
29. Lim JH KJ, Yoon IH, Shin JS, Nam HY, Yang SH, Kim SJ, Park CG. Immunomodulation of delayed-type hypersensitivity responses by mesenchymal stem cells is associated with bystander T cell apoptosis in the draining lymph node. J Immunol. 2010;185(7):4022-9.
30. Ge W JJ, Arp J, Liu W, Garcia B, Wang H. Regulatory T-cell generation and kidney allograft tolerance induced by mesenchymal stem cells associated with indoleamine 2,3-dioxygenase expression. Transplantation. 2010;90(11):1312-20.
31. Banchereau J SR. Dendritic cells and the control of immunity. Nature 1998;392(6673):245–52.
32. Ghannam S PJ, Torcy-Moquet G, Jorgensen C, Yssel H. Mesenchymal stem cells inhibit human Th17 cell differentiation and function and induce a T regulatory cell phenotype. J Immunol. 2010;185(6):302–12.
33. G Weinmaster. The ins and outs of notch signaling. Mol Cell Neurosci. 1997;9:91-102.
34. Eagar TN TQ, Wolfe M et al. Notch 1 signaling regulates peripheral T cell activation. Immunity. 2004;20(4):407- 15.
35. Rutz S MB, Sakano S et al. Notch ligands Delta-like1, Delta-like4 and Jagged1 differentially regulate activation of peripheral T helper cells. Eur J Immunol 2005;35:2443-51.
36. Pevsner-Fischer M MV, Cohen-Sfady M, Rousso-Noori L, Zanin-Zhorov A, Cohen S, Cohen IR, et al. Toll-like receptors and their ligands control mesenchymal stem cell functions. Blood. 2007;109(4):1422-32.
37. Tomchuck SL ZK, Coffelt SB, Waterman RS, Danka ES, Scandurro AB. . Toll-like receptors on human mesenchymal stem cells drive their migration and immunomodulating responses Stem Cells. 2008;26(1):99–107.
38. Liotta F AR, Cosmi L, Fili L, Manuelli C, Frosali F, Mazzinghi B, et al. Toll-like receptors 3 and 4 are expressed by human bone marrowderived mesenchymal stem cells and can inhibit their T-cell modulatory activity by impairing Notch signaling. Stem Cells. 2008;26(1):279–89.
39. Augello A TR, Negrini SM et al. Bone marrow mesenchymal progenitor cells inhibit lymphocyte proliferation by activation of the programmed death 1 pathway. Eur J Immunol. 2005;35(12):1482–90.
40. Lotfinegad P SK, Movassaghpour A.A, Majidi J, Baradaran B. Immunomodulatory Nature and Site Specific Affinity of Mesenchymal Stem Cells: a Hope in Cell Therapy. Adv Pharm Bull. 2014; 4(1):5–13.
2. Gluckman E RV, Boyer-Chammard A, Locatelli F, Arcese W, Pasquini R, Ortega J, Souillet G, Ferreira E, Laporte JP, Fernandez M, Chastang C. Outcome of cord-blood transplantation from related and unrelated donors. Eurocord Transplant Group and the European Blood and Marrow Transplantation Group. N Engl J Med. 1997;337(6):373-81.
3. Broxmeyer HE DG, Hangoc G, Cooper S, Bard J, English D, Arny M, Thomas L, Boyse EA. Human umbilical cord blood as a potential source of transplantable hematopoietic stem/progenitor cells. Proc Natl Acad Sci U S A. 1989;86(10):3828-32.
4. Dominici M LBK, Mueller I, Slaper-Cortenbach I, Marini F, Krause D, Deans R, Keating A, Prockop Dj, Horwitz E. Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy. 2006;8(4):315-7.
5. Swijnenburg RJ TM, Vogel H, Baker J, Kofidis T, Gunawan F, Lebl DR, Caffarelli AD, de Bruin JL, Fedoseyeva EV, Robbins RC. Embryonic stem cell immunogenicity increases upon differentiation after transplantation in to ischemic myocardium. Circulation. 2005;112(9):166-72.
6. In ‘t Anker PS SS, Kleijburg-van der Keur C, de Groot-Swings GM, Claas FH, Fibbe WE, Kanhai HH. Isolation of mesenchymal stem cells of fetal or maternal origin from human placenta. Stem Cells. 2004;22(4):1338-45.
7. Kim YJ BH. Immune regulatory cells in umbilical cord blood and their potential roles in transplantation tolerance. Crit Rev Oncol Hematol. 2011;79(2):112-26.
8. Wang M YY, Yang D, Luo F, Liang W, Guo S, Xu J. The immunomodulatory activity of human umbilical cord blood-derived mesenchymal stem cells in vitro. Immunology 2009;126(2):220-32.
9. Wang H-S HS-C, Peng S-T, et al. Mesenchymal stem cells in the Wharton’s jelly of the human umbilical cord. Stem Cells. 2004;22:1330-37.
10. Mazaheri T EA, H.KH. Mirzaei M. Introducing the immunomodulatory effects of mesenchymal stem cells in an experimental model of Behçet’s disease. Medical Hypotheses and Ideas 2012;6:23-7.
11. Nagamura-Inoue T HH. Umbilical cord-derived mesenchymal stem cells: Their advantages and potential clinical utility. World J Stem Cells. 2014;6(2):195-202.
12. A. Corcione FB, E. Ferretti et al. Human mesenchymal stem cells modulate B-cell functions. Blood. 2006;107(1):367-72.
13. A. Bartholomew CS, M. Siatskas et al. Mesenchymal stem cells suppress lymphocyte proliferation in vitro and prolong skin graft survival in vivo. Experimental Hematology. 2002;30(1):42-8.
14. C. Prevosto MZ, P. Canevali, M. R. Zocchi, and A. Poggi. Generation of CD4+ or CD8+ regulatory T cells upon mesenchymal stem cell-lymphocyte interaction. Haematologica. 2007;92(7):881-8.
15. Aggarwal S1 PM. Human mesenchymal stem cells modulate allogeneic immune cell responses. Blood. 2005;105(4):1815-22.
16. M. Di Nicola CC-S, M. Magni et al. Human bone marrow stromal cells suppress T-lymphocyte proliferation induced by cellular or nonspecific mitogenic stimuli. Blood. 2002;99(10):3838-43.
17. C. Campagnoli IAR, S. Kumar, P. R. Bennett, I. Bellantuono, and N. M. Fisk. Identification of mesenchymal stem/progenitor cells in human first-trimester fetal blood,liver, and bone marrow. Blood. 2001;98(8):2396-402.
18. Silva WA Jr CD, Panepucci RA, Proto-Siqueira R, Siufi JL, Zanette DL, Santos AR, Zago MA. The profile of gene expression of human marrow mesenchymal stem cells. Stem Cells. 2003;21(6):661-9.
19. Rezvany MR J-TM, Osterborg A, Kimby E, Wigzell H, Mellstedt H. Oligoclonal TCRBV Gene Usage in B-Cell Chronic Lymphocytic Leukemia: Major Perturbations Are Preferentially Seen Within the CD4 T-Cell Subset. Blood. 1999;94(3):1063-9.
20. Erices A CP, Minguell JJ. Mesenchymal progenitor cells in human umbilical cord blood. Br J Haematol. 2000;109(11):235-42.
21. Tipnis S VC, Majumdar AS. Immunosuppressive properties of human umbilical cord-derived mesenchymal stem cells: role of B7-H1 and IDO. Immunol Cell Biol. 2010 88(8):795-806.
22. Jin HJ NHY, Bae Y.K, Kim S.Y, Im I.R, Oh W, Yang Y.S, Choi S.J, Kim S.W. GD2 expression is closely associated with neuronal differentiation of human umbilical cord blood-derived mesenchymal stem cells. Cell Mol Life Sci. 2010;67(12):1845-58.
23. A J Engler SS, HL Sweeney, DE Discher. Matrix elasticity directs stem cell lineage specification. Cell Mol Life Sci. 2006;126(4): 677-89.
24. Divya MS RG, Divya TS, Rasheed VA, Santhoshkumar TR, Elizabeth KE, James J, Pillai RM. Umbilical cord blood-derived mesenchymal stem cells consist of a unique population of progenitors co-expressing mesenchymal stem cell and neuronal markers capable of instantaneous neuronal differentiation. Stem Cell Res Ther. 2012 3(6):57.
25. Zhang C CX, Zou ZM, Zhang X, Kong PY, Liang X, Gao L, Peng XG, Sun AH, Wang QY. Human umbilical cord blood-derived stromal cells suppress xenogeneic immune cell response in vitro. Croat Med J 2009;50:351-60.
26. Sakaguchi MM, Costantino CM,Hafler DA. FOXP3 + regulatory T cells in the human immune system. Immunol. 2010;10(4):490–500.
27. Fujimura T. YS, Taniguchi Y. et al. The induced regulatory T cell level, defined as the proportion of IL-10(+)Foxp3 (+) cells among CD25(+)CD4(+) leukocytes, is a potential therapeutic biomarker for sublingual immunotherapy: a preliminary report. Allergy Immunol. 2010;153(4):378–87.
28. Gonzalez MA G-RE, Rico L, Buscher D, Delgado M. Adiposederived mesenchymal stem cells alleviate experimental colitis by inhibiting inflammatory and autoimmune responses. Gastroenterology. 2009;136(4):978-89.
29. Lim JH KJ, Yoon IH, Shin JS, Nam HY, Yang SH, Kim SJ, Park CG. Immunomodulation of delayed-type hypersensitivity responses by mesenchymal stem cells is associated with bystander T cell apoptosis in the draining lymph node. J Immunol. 2010;185(7):4022-9.
30. Ge W JJ, Arp J, Liu W, Garcia B, Wang H. Regulatory T-cell generation and kidney allograft tolerance induced by mesenchymal stem cells associated with indoleamine 2,3-dioxygenase expression. Transplantation. 2010;90(11):1312-20.
31. Banchereau J SR. Dendritic cells and the control of immunity. Nature 1998;392(6673):245–52.
32. Ghannam S PJ, Torcy-Moquet G, Jorgensen C, Yssel H. Mesenchymal stem cells inhibit human Th17 cell differentiation and function and induce a T regulatory cell phenotype. J Immunol. 2010;185(6):302–12.
33. G Weinmaster. The ins and outs of notch signaling. Mol Cell Neurosci. 1997;9:91-102.
34. Eagar TN TQ, Wolfe M et al. Notch 1 signaling regulates peripheral T cell activation. Immunity. 2004;20(4):407- 15.
35. Rutz S MB, Sakano S et al. Notch ligands Delta-like1, Delta-like4 and Jagged1 differentially regulate activation of peripheral T helper cells. Eur J Immunol 2005;35:2443-51.
36. Pevsner-Fischer M MV, Cohen-Sfady M, Rousso-Noori L, Zanin-Zhorov A, Cohen S, Cohen IR, et al. Toll-like receptors and their ligands control mesenchymal stem cell functions. Blood. 2007;109(4):1422-32.
37. Tomchuck SL ZK, Coffelt SB, Waterman RS, Danka ES, Scandurro AB. . Toll-like receptors on human mesenchymal stem cells drive their migration and immunomodulating responses Stem Cells. 2008;26(1):99–107.
38. Liotta F AR, Cosmi L, Fili L, Manuelli C, Frosali F, Mazzinghi B, et al. Toll-like receptors 3 and 4 are expressed by human bone marrowderived mesenchymal stem cells and can inhibit their T-cell modulatory activity by impairing Notch signaling. Stem Cells. 2008;26(1):279–89.
39. Augello A TR, Negrini SM et al. Bone marrow mesenchymal progenitor cells inhibit lymphocyte proliferation by activation of the programmed death 1 pathway. Eur J Immunol. 2005;35(12):1482–90.
40. Lotfinegad P SK, Movassaghpour A.A, Majidi J, Baradaran B. Immunomodulatory Nature and Site Specific Affinity of Mesenchymal Stem Cells: a Hope in Cell Therapy. Adv Pharm Bull. 2014; 4(1):5–13.
| Files | ||
| Issue | Vol 20 No 6 (2021) | |
| Section | Original Article(s) | |
| DOI | https://doi.org/10.18502/ijaai.v20i6.8022 | |
| Keywords | ||
| Cytokines Immunomodulation Mesenchymal stem cells T-lymphocytes | ||
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How to Cite
1.
Lotfinejad P, Shamsasenjan K, Baradaran B, Safarzadeh E, Kazemi T, Movassaghpour AA. Immunomodulatory Effect of Human Umbilical Cord Blood-derived Mesenchymal Stem Cells on Activated T-lymphocyte. Iran J Allergy Asthma Immunol. 2021;20(6):711-720.
