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Nikoo, S., Ebtekar, M., Jeddi-Tehrani, M., Bozorgmehr, M., & Zarnani, A.-H. (2021). Culture density of menstrual blood-derived stromal/stem cells determines the quality of T cell responses: An experimental study. International Journal of Reproductive BioMedicine (IJRM), 19(1), 75–86. https://doi.org/10.18502/ijrm.v19i1.8182
https://doi.org/10.18502/ijrm.v19i1.8182
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authors
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Shohreh Nikoo
Shohreh Nikoo
Immunology Research Center, Iran University of Medical Sciences, Tehran, Iran
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Massoumeh Ebtekar
Massoumeh Ebtekar
Department of Immunology, Faculty of Medicine, Tarbiat Modares University, Tehran, Iran
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Mahmood Jeddi-Tehrani
Mahmood Jeddi-Tehrani
Monoclonal Antibody Research Center, Avicenna Research Institute, ACECR, Tehran, Iran
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Mahmood Bozorgmehr
Mahmood Bozorgmehr
Reproductive Immunology Research Center, Avicenna Research Institute, ACECR, Tehran, Iran
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Amir-Hassan Zarnani
Amir-Hassan Zarnani
Reproductive Immunology Research Center, Avicenna Research Institute, ACECR, Tehran, Iran
Published Date
- Jan 25, 2021
Culture density of menstrual blood-derived stromal/stem cells determines the quality of T cell responses: An experimental study
Abstract
Background: Menstrual blood-derived stromal/stem cells (MenSCs) are a new population of refreshing and highly proliferative stem cells. Immunomodulatory effects of MenSCs profoundly depend on their relative density.
Objective: To find whether MenSCs cultured at varying numbers would differentially affect the allogenic peripheral blood mononuclear cells (PBMCs) key features.
Materials and Methods: PBMCs were co-cultured with various MenSCs numbers. PBMCs proliferation was investigated via 3H-thymidine incorporation. Flow cytometry was used to assess human leukocyte antigen (HLA)-DR, HLA-ABC, HLA-G, and costimulatory markers on MenSCs and the percentage of regulatory T cells (Tregs) among PBMCs. The concentration of cytokines was determined in supernatant of co-cultures.
Results: The support of PBMCs proliferation at low MenSCs densities correlated with higher levels of pro-inflammatory interferon gamma (IFN-γ) in MenSCs/PBMCs co-culture and increased expression of HLA-DR by MenSCs. On the other hand, the suppressive property of MenSCs at higher densities was independent of Treg frequency, but correlated with a high concentration of Interleukin (IL)-6 and IL-10 in the co-cultures.
Conclusion: Totally, at different seeding densities, MenSCs could differentially interact with PBMCs leading to significant changes in the level of anti- and/or pro-inflammatory factors. These preliminary in vitro results are suggested to be taken into consideration in experimental models of MenSC-based immunomodulation. Nonetheless, for efficient utilization of MenSCs anti-inflammatory features in pre-clinical disease models, we still need to broaden our knowledge on MenSC-immune system cross-talk; this could play a part in designing more optimized MenSCs injection modalities in the case of future pre-clinical and subsequently clinical settings.
Key words: Menstrual, Stromal cells, T cell response, Interferon-
References
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[17] Khoury M, Alcayaga-Miranda F, Illanes SE, Figueroa FE. The promising potential of menstrual stem cells for antenatal diagnosis and cell therapy. Front Immunol 2014; 5: 205–212.
[18] Joo SY, Cho KA, Jung YJ, Kim HS, Park SY, Choi YB, et al. Mesenchymal stromal cells inhibit graft-versushost disease of mice in a dose-dependent manner. Cytotherapy 2010; 12: 361–370.
[19] Chan JL, Tang KC, Patel AP, Bonilla LM, Pierobon N, Ponzio NM, et al. Antigen-presenting property of mesenchymal stem cells occurs during a narrow window at low levels of interferon-γ. Blood 2006; 107: 4817–4824.
[20] Wang H, Jin P, Sabatino M, Ren J, Civini S, Bogin V, et al. Comparison of endometrial regenerative cells and bone marrow stromal cells. J Transl Med 2012; 10: 207–220.
[21] Akira Sh, Hirano T, Taga T, Kishimoto T. Biology of multifunctional cytokines: IL 6 and related molecules (IL 1 and TNF). FASEB J 1990; 4: 2860–2867.
[22] Del Prete G, De Carli M, Almerigogna F, Giudizi MG, Biagiotti R, Romagnani S. Human IL-10 is produced by both type 1 helper (Th1) and type 2 helper (Th2) T cell clones and inhibits their antigen-specific proliferation and cytokine production. J Immunol 1993; 150: 353–360.
[23] Melief SM, Schrama E, Brugman MH, Tiemessen MM, Hoogduijn MJ, Fibbe WE, et al. Multipotent stromal cells induce human regulatory T cells through a novel pathway involving skewing of monocytes toward anti−inflammatory macrophages. Stem Cells 2013; 31: 1980–1991.
[24] Aggarwal S, Pittenger MF. Human mesenchymal stem cells modulate allogeneic immune cell responses. Blood 2005; 105: 1815–1822.
[25] Xing Z, Gauldie J, Cox G, Baumann H, Jordana M, Lei XF, et al. IL-6 is an antiinflammatory cytokine required for controlling local or systemic acute inflammatory responses. J Clin Invest 1998; 101: 311–320.
[26] Eljaafari A, Tartelin ML, Aissaoui H, Chevrel G, Osta B, Lavocat F, et al. Bone marrow-derived and synovium−derived mesenchymal cells promote Th17 cell expansion and activation through caspase 1 activation: Contribution to the chronicity of rheumatoid arthritis. Arthritis Rheum 2012; 64: 2147–2157.
[27] Guo Zh, Zheng C, Chen Zh, Gu D, Du W, Ge J, et al. Fetal BM−derived mesenchymal stem cells promote the expansion of human Th17 cells, but inhibit the production of Th1 cells. Eur J Immunol 2009; 39: 2840–2849.
[28] Desai MB, Gavrilova T, Liu J, Patel SA, Kartan S, Greco SJ, et al. Pollen-induced antigen presentation by mesenchymal stem cells and T cells from allergic rhinitis. Clin Transl Immunol 2013; 2: e7. 1–9.
[29] Selmani Z, Naji A, Zidi I, Favier B, Gaiffe E, Obert L, et al. Human leukocyte antigen−G5 secretion by human mesenchymal stem cells is required to suppress T lymphocyte and natural killer function and to induce CD4+ CD25highFOXP3+ regulatory T cells. Stem Cells 2008; 26: 212–222.
[30] Bernardo ME, Fibbe WE. Mesenchymal stromal cells: sensors and switchers of inflammation. Cell Stem Cell 2013; 13: 392–402.
[31] Chang ChJ, Yen ML, Chen YCh, Chien ChCh, Huang HI, Bai ChH, et al. Placenta−derived multipotent cells exhibit immunosuppressive properties that are enhanced in the presence of interferon−γ. Stem Cells 2006; 24: 2466– 2477.
[32] Chen PM, Yen ML, Liu KJ, Sytwu HK, Yen BL. Immunomodulatory properties of human adult and fetal multipotent mesenchymal stem cells. J Biomed Sci 2011; 18: 49–59.
[33] Voo KS, Wang YH, Santori FR, Boggiano C, Wang YH, Arima K, et al. Identification of IL-17-producing FOXP3+ regulatory T cells in humans. Proc Natl Acad Sci USA 2009; 106: 4793–4798.
[34] Ayyoub M, Deknuydt F, Raimbaud I, Dousset C, Leveque L, Bioley G, et al. Human memory FOXP3+ Tregs secrete IL-17 ex vivo and constitutively express the TH17 lineagespecific transcription factor RORγt. Proc Natl Acad Sci USA 2009; 106: 8635–8640.
[35] Nasef A, Mathieu N, Chapel A, Frick J, François S, Mazurier C, et al. Immunosuppressive effects of mesenchymal stem cells: involvement of HLA-G. Transplantation 2007; 84: 231–237.
[2] Brooke G, Cook M, Blair Ch, Han R, Heazlewood C, Jones B, et al. Therapeutic applications of mesenchymal stromal cells. Semin Cell Dev Biol 2007; 18: 846–858.
[3] Ghannam S, Pene J, Moquet-Torcy 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: 302–312.
[4] Le Blanc K, Tammik Ch, Rosendahl K, Zetterberg E, Ringden O. HLA expression and immunologic properties of differentiated and undifferentiated mesenchymal stem cells. Exp Hematol 2003; 31: 890–896.
[5] Maccario R, Podesta M, Moretta A, Cometa A, Comoli P, Montagna D, et al. Interaction of human mesenchymal stem cells with cells involved in alloantigen-specific immune response favors the differentiation of CD4+ T-cell subsets expressing a regulatory/suppressive phenotype. Haematologica 2005; 90: 516–525.
[6] Kern S, Eichler H, Stoeve J, Klüter H, Bieback K. Comparative analysis of mesenchymal stem cells from bone marrow, umbilical cord blood, or adipose tissue. Stem Cells 2006; 24: 1294–1301.
[7] Nikoo Sh, Ebtekar M, Jeddi-Tehrani M, Shervin A, Bozorgmehr M, Kazemnejad S, et al. Effect of menstrual blood-derived stromal stem cells on proliferative capacity of peripheral blood mononuclear cells in allogeneic mixed lymphocyte reaction. J Obstet Gynaecol Res 2012; 38: 804–809.
[8] Kazemnejad S, Zarnani AH, Khanmohammadi M, Mobini S. Chondrogenic differentiation of menstrual blood-derived stem cells on nanofibrous scaffolds. In: Turksen K, editor. Stem Cell Nanotechnology: Methods and Protocols. Totowa, NJ: Humana Press; 2013. p. 149–69.
[9] Nikoo Sh, Ebtekar M, Jeddi-Tehrani M, Shervin A, Bozorgmehr M, Vafaei S, et al. Menstrual blood-derived stromal stem cells from women with and without endometriosis reveal different phenotypic and functional characteristics. Mol Hum Reprod 2014; 20: 905–918.
[10] Murphy MP, Wang H, Patel AN, Kambhampati S, Angle N, Chan K, et al. Allogeneic endometrial regenerative cells: an “off the shelf solution” for critical limb ischemia? J Translat Med 2008; 6: 45–52.
[11] Najar M, Rouas R, Raicevic G, Boufker HI, Lewalle P, Meuleman N, et al. Mesenchymal stromal cells promote or suppress the proliferation of T lymphocytes from cord blood and peripheral blood: the importance of low cell ratio and role of interleukin-6. Cytotherapy 2009; 11: 570– 583.
[12] Fang L, Lange C, Engel M, Zander AR, Fehse B. Sensitive balance of suppressing and activating effects of mesenchymal stem cells on T-cell proliferation. Transplantation 2006; 82: 1370–1373.
[13] Bozorgmehr M, Moazzeni SM, Salehnia M, Sheikhian A, Nikoo Sh, Zarnani AH. Menstrual blood-derived stromal stem cells inhibit optimal generation and maturation of human monocyte-derived dendritic cells. Immunol Lett 2014; 162: 239–246.
[14] Zhong Zh, Patel AN, Ichim ThE, Riordan NH, Wang H, Min WP, et al. Feasibility investigation of allogeneic endometrial regenerative cells. J Transl Med 2009; 7: 15–21.
[15] Lv Y, Xu X, Zhang B, Zhou G, Li H, Du C, et al. Endometrial regenerative cells as a novel cell therapy attenuate experimental colitis in mice. J Transl Med 2014; 12: 344–354.
[16] Luz−Crawford P, Torres MJ, Noël D, Fernandez A, Toupet K, Alcayaga−Miranda F, et al. The immunosuppressive signature of menstrual blood mesenchymal stem cells entails opposite effects on experimental arthritis and graft versus host diseases. Stem Cells 2016; 34: 456–469.
[17] Khoury M, Alcayaga-Miranda F, Illanes SE, Figueroa FE. The promising potential of menstrual stem cells for antenatal diagnosis and cell therapy. Front Immunol 2014; 5: 205–212.
[18] Joo SY, Cho KA, Jung YJ, Kim HS, Park SY, Choi YB, et al. Mesenchymal stromal cells inhibit graft-versushost disease of mice in a dose-dependent manner. Cytotherapy 2010; 12: 361–370.
[19] Chan JL, Tang KC, Patel AP, Bonilla LM, Pierobon N, Ponzio NM, et al. Antigen-presenting property of mesenchymal stem cells occurs during a narrow window at low levels of interferon-γ. Blood 2006; 107: 4817–4824.
[20] Wang H, Jin P, Sabatino M, Ren J, Civini S, Bogin V, et al. Comparison of endometrial regenerative cells and bone marrow stromal cells. J Transl Med 2012; 10: 207–220.
[21] Akira Sh, Hirano T, Taga T, Kishimoto T. Biology of multifunctional cytokines: IL 6 and related molecules (IL 1 and TNF). FASEB J 1990; 4: 2860–2867.
[22] Del Prete G, De Carli M, Almerigogna F, Giudizi MG, Biagiotti R, Romagnani S. Human IL-10 is produced by both type 1 helper (Th1) and type 2 helper (Th2) T cell clones and inhibits their antigen-specific proliferation and cytokine production. J Immunol 1993; 150: 353–360.
[23] Melief SM, Schrama E, Brugman MH, Tiemessen MM, Hoogduijn MJ, Fibbe WE, et al. Multipotent stromal cells induce human regulatory T cells through a novel pathway involving skewing of monocytes toward anti−inflammatory macrophages. Stem Cells 2013; 31: 1980–1991.
[24] Aggarwal S, Pittenger MF. Human mesenchymal stem cells modulate allogeneic immune cell responses. Blood 2005; 105: 1815–1822.
[25] Xing Z, Gauldie J, Cox G, Baumann H, Jordana M, Lei XF, et al. IL-6 is an antiinflammatory cytokine required for controlling local or systemic acute inflammatory responses. J Clin Invest 1998; 101: 311–320.
[26] Eljaafari A, Tartelin ML, Aissaoui H, Chevrel G, Osta B, Lavocat F, et al. Bone marrow-derived and synovium−derived mesenchymal cells promote Th17 cell expansion and activation through caspase 1 activation: Contribution to the chronicity of rheumatoid arthritis. Arthritis Rheum 2012; 64: 2147–2157.
[27] Guo Zh, Zheng C, Chen Zh, Gu D, Du W, Ge J, et al. Fetal BM−derived mesenchymal stem cells promote the expansion of human Th17 cells, but inhibit the production of Th1 cells. Eur J Immunol 2009; 39: 2840–2849.
[28] Desai MB, Gavrilova T, Liu J, Patel SA, Kartan S, Greco SJ, et al. Pollen-induced antigen presentation by mesenchymal stem cells and T cells from allergic rhinitis. Clin Transl Immunol 2013; 2: e7. 1–9.
[29] Selmani Z, Naji A, Zidi I, Favier B, Gaiffe E, Obert L, et al. Human leukocyte antigen−G5 secretion by human mesenchymal stem cells is required to suppress T lymphocyte and natural killer function and to induce CD4+ CD25highFOXP3+ regulatory T cells. Stem Cells 2008; 26: 212–222.
[30] Bernardo ME, Fibbe WE. Mesenchymal stromal cells: sensors and switchers of inflammation. Cell Stem Cell 2013; 13: 392–402.
[31] Chang ChJ, Yen ML, Chen YCh, Chien ChCh, Huang HI, Bai ChH, et al. Placenta−derived multipotent cells exhibit immunosuppressive properties that are enhanced in the presence of interferon−γ. Stem Cells 2006; 24: 2466– 2477.
[32] Chen PM, Yen ML, Liu KJ, Sytwu HK, Yen BL. Immunomodulatory properties of human adult and fetal multipotent mesenchymal stem cells. J Biomed Sci 2011; 18: 49–59.
[33] Voo KS, Wang YH, Santori FR, Boggiano C, Wang YH, Arima K, et al. Identification of IL-17-producing FOXP3+ regulatory T cells in humans. Proc Natl Acad Sci USA 2009; 106: 4793–4798.
[34] Ayyoub M, Deknuydt F, Raimbaud I, Dousset C, Leveque L, Bioley G, et al. Human memory FOXP3+ Tregs secrete IL-17 ex vivo and constitutively express the TH17 lineagespecific transcription factor RORγt. Proc Natl Acad Sci USA 2009; 106: 8635–8640.
[35] Nasef A, Mathieu N, Chapel A, Frick J, François S, Mazurier C, et al. Immunosuppressive effects of mesenchymal stem cells: involvement of HLA-G. Transplantation 2007; 84: 231–237.