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Factors governing the immunosuppressive effects of multipotent mesenchymal stromal cells in vitro

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Abstract

Multipotent mesenchymal stem/stromal cells (MSCs) are of great interest to researchers because of the unique properties, such as enhanced proliferation, paracrine activity and multilineage differentiation. Their non-immunogenicity, in combination with immunomodulatory properties, opens up the opportunity for the allogeneic application of MSCs. The MSC immunomodulatory capacity is currently being actively studied in vitro using various experimental designs. However, the results are not always univocal. It was found that the outcome of the stromal/immune cell interaction depends on experimental conditions. In this review we considered the impact of different factors, such as the ratio of stromal/immune cells, interaction time, the path of immune cell activation, etc. on the MSC immunomodulation. We also accentuated the importance of local milieu, in particular, oxygen tension, for the realization of MSC immunosuppressive activity.

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References

  • Aggarwal S, Pittenger MF (2005) Human mesenchymal stem cells modulate allogeneic immune cell responses. Blood 105:1815–1822

    Article  CAS  Google Scholar 

  • Andreeva ER, Grigorieva OV, Andrianova IV, Gornostaeva AN, Buravkova LB (2012) Human stromal and blood-born cells interaction under different O2 tension. part I. Immunocupressive effects. Technol Living Syst 9:13–18

    CAS  Google Scholar 

  • Ankrum JA, Ong JF, Karp JM (2014) Mesenchymal stem cells: immune evasive, not immune privileged. Nat Biotechnol 32:252–260

    Article  CAS  Google Scholar 

  • Bartholomew A, Sturgeon C, Siatskas M et al (2002) Mesenchymal stem cells suppress lymphocyte proliferation in vitro and prolong skin graft survival in vivo. Exp Hematol 30:42–48

    Article  Google Scholar 

  • Benvenuto F, Ferrari S, Gerdoni E et al (2007) Human mesenchymal stem cells promote survival of T cells in a quiescent state. Stem Cells 25:1753–1760

    Article  CAS  Google Scholar 

  • Buravkova LB, Grinakovskaia OS, Andreeva EP, Zhambalova AP, Kozionova MP (2009) Characteristics of human lipoaspirate-isolated mesenchymal stromal cells cultivated under a lower oxygen tension. Tsitologiia 51:5–11

    CAS  Google Scholar 

  • Caplan AI (2009) Why are MSCs therapeutic? New data: new insight. J Pathol 217:318–324

    Article  CAS  Google Scholar 

  • Cappellesso-Fleury S, Puissant B, Apoil PA et al (2010) Human fibroblasts share immunosuppressive properties with bone marrow mesenchymal stem cells. J Clin Immunol 30:607–619

    Article  Google Scholar 

  • Carrade Holt DD, Wood JA, Granick JL et al (2014) Equine mesenchymal stem cells inhibit T cell proliferation through different mechanisms depending on tissue source. Stem Cells Dev 23:1258–1265

    Article  CAS  Google Scholar 

  • Chabannes D, Hill M, Merieau E et al (2007) A role for heme oxygenase-1 in the immunosuppressive effect of adult rat and human mesenchymal stem cells. Blood 110:3691–3694

    Article  CAS  Google Scholar 

  • Corcione A, Benvenuto F, Ferretti E et al (2006) Human mesenchymal stem cells modulate B-cell functions. Blood 107:367–372

    Article  CAS  Google Scholar 

  • Crop M, Baan CC, Korevaar SS et al (2010) Human adipose tissue-derived mesenchymal stem cells induce explosive T-cell proliferation. Stem Cells Dev 19:1843–1853

    Article  CAS  Google Scholar 

  • Deng W, Han Q, Liao L et al (2005) Effects of allogeneic bone marrow-derived mesenchymal stem cells on T and B lymphocytes from BXSB mice. DNA Cell Biol 24:458–463

    Article  CAS  Google Scholar 

  • Dominici M, Le Blanc K, Mueller I et al (2006) Minimal criteria for defining multipotent mesenchymal stromal cells. Cytotherapy 8:315–317

    Article  CAS  Google Scholar 

  • Engela AU, Baan CC, Dor Frank JMF et al (2012) On the interactions between mesenchymal stem cells and regulatory T cells for immunomodulation in transplantation. Front Immunol 3:126–134

    Article  Google Scholar 

  • Fehrer C, Brunauer R, Laschober G et al (2007) Reduced oxygen tension attenuates differentiation capacity of human mesenchymal stem cells and prolongs their lifespan. Aging Cell 6:745–757

    Article  CAS  Google Scholar 

  • Francois M, Romieu-Mourez R, Li M, Galipeau J (2012) Human MSC suppression correlates with cytokine induction of indoleamine 2,3-dioxygenase and bystander M2 macrophage differentiation. Mol Ther 20:187–195

    Article  CAS  Google Scholar 

  • Friedenstein AJ, Chailakhjan RK, Lalykina KS (1970) The development of fibroblast colonies in monolayer cultures of guinea-pig bone marrow and spleen cells. Cell Tissue Kinet 3:393–403

    CAS  Google Scholar 

  • Glennie S, Soeiro I, Dyson PJ et al (2005) Bone marrow mesenchymal stem cells induce division arrest anergy of activated T cells. Blood 105:2821–2827

    Article  CAS  Google Scholar 

  • Gornostaeva AN, Andreeva ER, Andrianova IV, Buravkova LB (2011) Immunosuppressive effects of multipotent mesenchymal stromal cells in cultures with different O2 content in the medium. Bull Exp Biol Med 151:526–529

    Article  CAS  Google Scholar 

  • Gornostaeva AN, Andreeva ER, Buravkova LB (2013) Human MMSC immunosuppressive activity at low oxygen tension: direct cell-to-cell contacts and paracrine regulation. Hum Physiol 39:31–42

    Article  CAS  Google Scholar 

  • Grayson WL, Zhao F, Bunnell B, Ma T (2007) Hypoxia enhances proliferation and tissue formation of human mesenchymal stem cells. Biochem Biophys Res Commun 358:948–953

    Article  CAS  Google Scholar 

  • Grigoryan AS, Tsupkina NV, Sergeev VS et al (2007) Characterization of bone marrow stromal cells in the mixed lymphocyte reaction. Cell Transplantol Tissue Eng 2:62–66

    Google Scholar 

  • Groh ME, Maitra B, Szekely E, Koc ON (2005) Human mesenchymal stem cells require monocyte-mediated activation to suppress alloreactive T cells. Exp Hematol 33:928–934

    Article  CAS  Google Scholar 

  • Huang XP, Sun Z, Miyagi Y et al (2010) Differentiation of allogeneic mesenchymal stem cells induces immunogenicity and limits their long-term benefits for myocardial repair. Circulation 122:2419–2429

    Article  CAS  Google Scholar 

  • Ja Friedenstein A, Luria EA (1980) Cellular bases of hemopoietic microenviroment. Meditsina, Moscow

    Google Scholar 

  • Jarvinen L, Badri L, Wettlaufer S et al (2008) Lung resident mesenchymal stem cells isolated from human lung allografts inhibit T cell proliferation via a soluble mediator. J Immunol. 181:4389–4396

    Article  CAS  Google Scholar 

  • Jiang XX, Zhang Y, Liu B et al (2005) Human mesenchymal stem cells inhibit differentiation and function of monocyte-derived dendritic cells. Blood 105:4120–4126

    Article  CAS  Google Scholar 

  • Jones BJ, McTaggart J (2008) Immunosuppression by mesenchymal stromal cells: From culture to clinic. Exp Hematol 36:733–741

    Article  CAS  Google Scholar 

  • Kim JH, Lee YT, Hong JM, Hwang YI (2013) 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 46:262–271

    Article  Google Scholar 

  • Kim DS, Lee MW, Yoo KH et al (2014) gene expression profiles of human adipose tissue-derived mesenchymal stem cells are modified by cell culture density. PLoS One 9:e83363. doi:10.1371/journal.pone.0083363

    Article  Google Scholar 

  • Krampera M, Cosmi L, Angeli R et al (2006) Role for interferon-gamma in the immunomodulatory activity of human bone marrow mesenchymal stem cells. Stem Cells 24:386–398

    Article  CAS  Google Scholar 

  • Kronsteiner B, Wolbank S, Peterbauer A et al (2011) Human mesenchymal stem cells from adipose tissue and amnion influence T-cells depending on stimulation method and presence of other immune cells. Stem Cells Dev 20:2115–2126

    Article  CAS  Google Scholar 

  • Le Blanc K, Tammik C, Rosendahl K et al (2003a) b) HLA expression and immunologic properties of differentiated and undifferentiated mesenchymal stem cells. Exp Hematol 31:890–896

    Article  Google Scholar 

  • Le Blanc K, Tammik L, Sundberg B et al (2003b) Mesenchymal stem cells inhibit and stimulate mixed lymphocyte cultures and mitogenic responses independently of the major histocompatibility complex. Scand J Immunol 57:11–20

    Article  Google Scholar 

  • Le Blanc K, Rasmusson I, Gotherstrom C et al (2004) Mesenchymal stem cells inhibit the expression of CD25 (interleukin-2 receptor) and CD38 on phytohaemagglutinin-activated lymphocytes. Scand J Immunol 60:307–315

    Article  Google Scholar 

  • Le Blanc K, Frassoni F, Ball L et al (2008) Mesenchymal stem cells for treatment of steroid-resistant, severe, acute graft-versus-host disease: a phase II study. Lancet 371:1579–1586

    Article  Google Scholar 

  • Lee MW, Kim DS, Ryu S et al (2013) Effect of ex vivo culture conditions on immunosuppression by human mesenchymal stem cells. Biomed Res Int 2013:154919. doi:10.1155/2013/154919

    Google Scholar 

  • Lin CS, Lin G, Lue TF (2012) Allogeneic and xenogeneic transplantation of adipose-derived stem cells in immunocompetent recipients without immunosuppressants. Stem Cells Dev 12:2770–2778

    Article  Google Scholar 

  • Maccario R, Podesta M, Moretta A et al (2005) 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. Stem Cell Transplant Haematol 90:516–525

    CAS  Google Scholar 

  • Mcintosh K, Zvonic S, Garrett S et al (2006) The immunogenicity of human adipose-derived cells: temporal changes in vitro. Stem Cells 24:1246–1253

    Article  CAS  Google Scholar 

  • Meisel R, Zibert A, Laryea M et al (2004) Human bone marrow stromal cells inhibit allogeneic T-cell responses by indoleamine 2,3-dioxygenase–mediated tryptophan degradation. Blood 103:4619–4621

    Article  CAS  Google Scholar 

  • Nauta AJ, Kruisselbrink AB, Lurvink E et al (2006) Mesenchymal stem cells inhibit generation and function of both CD34-derived and monocyte-derived dendritic cells. J Immunol 177:2080–2087

    Article  CAS  Google Scholar 

  • Nekanti U, Dastidar S, Venugopal P et al (2010) Increased proliferation and analysis of differential gene expression in human wharton’s jelly-derived mesenchymal stromal cells under hypoxia. Cell 6:499–512

    CAS  Google Scholar 

  • Niemeyer P, Vohrer J, Schmal H et al (2008) Survival of human mesenchymal stromal cells from bone marrow and adipose tissue after xenogenic transplantation in immunocompetent mice. Cytotherapy 10:784–795

    Article  CAS  Google Scholar 

  • Orkin SH, Zon LI (2008) Hematopoiesis: an evolving paradigm for stem cell biology. Cell 132:631–644

    Article  CAS  Google Scholar 

  • Park MJ, Shin JS, Kim YH et al (2011) Murine mesenchymal stem cells suppress T lymphocyte activation through IL-2 receptor α (CD25) cleavage by producing matrix metalloproteinases. Stem Cell Rev 7:381–393

    Article  CAS  Google Scholar 

  • Pigotta JH, Ishiharaa A, Wellmanb ML et al (2013) Investigation of the immune response to autologous, allogeneic, and xenogeneic mesenchymal stem cells after intra-articular injection in horses. Vet Immunol Immunopathol 156:99–106

    Article  Google Scholar 

  • Prasanna SJ, Gopalakrishnan D, Shankar SR, Vasandan AB (2010) Pro-Inflammatory cytokines, IFNγ and TNFa, influence immune properties of human bone marrow and wharton jelly mesenchymal stem cells differentially. PLoS One 5:e9016

    Article  Google Scholar 

  • Puissant B, Barreau C, Bourin P et al (2005) Immunomodulatory effect of human adipose tissue-derived adult stem cells: comparison with bone marrow mesenchymal stem cells. Br J Haematol 129:118–129

    Article  Google Scholar 

  • Quaedackers ME, Baan CC, Weimar W, Hoogduijn MJ (2009) Cell contact interaction between adipose-derived stromal cells and allo-activated T lymphocytes. Eur J Immunol 39:3436–3446

    Article  CAS  Google Scholar 

  • Ramasamy R, Tong CK, Seow HF et al (2008) The immunosuppressive effects of human bone marrow-derived mesenchymal stem cells target T-cell proliferation but not its effector function. Cell Immunol 251:131–136

    Article  CAS  Google Scholar 

  • Ren G, Su J, Zhang L et al (2009) Species variation in the mechanisms of mesenchymal stem cell-mediated immunosuppression. Stem Cells 27:1954–1962

    Article  CAS  Google Scholar 

  • Ryan JM, Barry F, Murphy JM, Mahon BP (2007) Interferon-gamma does not break, but promotes the immunosuppressive capacity of adult human mesenchymal stem cells. Clin Exp Immunol 149:353–363

    Article  CAS  Google Scholar 

  • Saldanha-Araujo F, Haddad R, Kelen CR et al (2012) Mesenchymal stem cells promote the sustained expression of CD69 on activated T lymphocytes: roles of canonical and non-canonical NF-kB signaling. J Cell Mol Med 16:1232–1244

    Article  CAS  Google Scholar 

  • Selmani Z, Naji A, Zidi I et al (2008) Human leukocyte antigen-G5 secretion by human mesenchymal stem cells is required to suppress t lymphocyte and natural killer function and to induce CD4-CD25 high FOXP3- regulatory T cells. Stem Cells 26:212–222

    Article  CAS  Google Scholar 

  • Shi Y, Su J, Roberts AI, Shou P, Rabson AB, Ren G (2012) How mesenchymal stem cells interact with tissue immune responses. Trends Immunol 33:136–143

    Article  CAS  Google Scholar 

  • Sotiropoulou PA, Perez SA, Gritzapis AD, Baxevanis CN, Papamichail M (2006) Interactions between human mesenchymal stem cells and natural killer cells. Stem Cells 24:74–85

    Article  Google Scholar 

  • Spaggiari GM, Capobianco A, Becchetti S et al (2006) Mesenchymal stem cell-natural killer cell interactions: evidence that activated NK cells are capable of killing MSCs, whereas MSCs can inhibit IL-2-induced NK-cell proliferation. Blood 107:1484–1490

    Article  CAS  Google Scholar 

  • Suva D, Passweg J, Arnaudeau S et al (2008) In vitro activated human t lymphocytes very efficiently attach to allogenic multipotent mesenchymal stromal cells and transmigrate under them. J Cell Physiol 214:588–594

    Article  CAS  Google Scholar 

  • Tasso R, Ilengo C, Quarto R et al (2012) Mesenchymal stem cells induce functionally active T-regulatory lymphocytes in a paracrine fashion and ameliorate experimental autoimmune uveitis. Invest Ophthalmol Vis Sci 53:786–793

    Article  CAS  Google Scholar 

  • Yang SH, Park MJ, Yoon IH et al (2009) Soluble mediators from mesenchymal stem cells supress T cell proliferation by inducing IL-10. Exp Mol Med 41:315–324

    Article  CAS  Google Scholar 

  • Zappia E, Casazza S, Pedemonte E et al (2005) Mesenchymal stem cells ameliorate experimental autoimmune encephalomyelitis inducing T-cell anergy. Blood 106:1755–1761

    Article  CAS  Google Scholar 

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Funding

This study was funded by Grant RFBR 13-04-00791, Grant RFBR 14-04-31362 mol_a and grant of the President of the Russian Federation SP-3502.2015.4.

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Authors and Affiliations

  1. Institute of Biomedical Problems of RAS, Khoroshevskoye Shosse, 76 a, Moscow, Russia, 123007

    Aleksandra Gornostaeva, Elena Andreeva & Ludmila Buravkova

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  1. Aleksandra Gornostaeva
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  2. Elena Andreeva
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  3. Ludmila Buravkova
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Correspondence to Aleksandra Gornostaeva.

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Gornostaeva, A., Andreeva, E. & Buravkova, L. Factors governing the immunosuppressive effects of multipotent mesenchymal stromal cells in vitro. Cytotechnology 68, 565–577 (2016). https://doi.org/10.1007/s10616-015-9906-5

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  • DOI: https://doi.org/10.1007/s10616-015-9906-5

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