Immunomodulatory Effects of Multipotent Mesenchymal Stromal Cells on T-Cell Populations at Tissue-Related Oxygen Level

Multipotent mesenchymal stromal cells (MSCs)
possess immunomodulatory properties. The effect of MSCs on the
crucial cellular immunity compartment – T-cells is of a special
interest. It is known that MSC tissue niche and expected milieu of
their interaction with T- cells are characterized by low oxygen
concentration, whereas the in vitro experiments usually are carried
out at a much higher ambient oxygen (20%). We firstly evaluated
immunomodulatory effects of MSCs on T-cells at tissue-related
oxygen (5%) after interaction implied cell-to-cell contacts and
paracrine factors only. It turned out that MSCs under reduced oxygen
can effectively suppress the activation and proliferation of PHAstimulated
T-cells and can provoke decrease in the production of
proinflammatory and increase in anti-inflammatory cytokines. In
hypoxia some effects were amplified (inhibition of proliferation, antiinflammatory
cytokine profile shift). This impact was more evident
after direct cell-to-cell interaction; lack of intercellular contacts could
revoke the potentiating effect of hypoxia.





References:
[1] D. Suva, J. Passweg, S. Arnaudeau, P. Hoffmeyer, and V. Kindler, "In
vitro activated human T lymphocytes very efficiently attach to allogenic
multipotent mesenchymal stromal cells and transmigrate under them”, J.
Cell. Physiol, vol. 214, pp. 588–594, 2008.
[2] S. Tabera, J. A. Pérez-Simón, M. Díez-Campelo, L. I. Sánchez-Abarca,
B. Blanco, A. López, et al., "The effect of mesenchymal stem cells on
the viability, proliferation and differentiation of B-lymphocytes”,
Haematologica, vol. 93, pp. 1301-1309, 2008.
[3] S. H. Yang, M. J. Park, I. H. Yoon, S. Y. Kim, S. H. Hong, J. Y. Shin, et
al., "Soluble mediators from mesenchymal stem cells supress T cell
proliferation by inducing IL-10”, Exp. Mol. Med., vol. 41, pp. 315-324,
2009.
[4] B. Kronsteiner, S. Wolbank, A. Peterbauer, C. Hackl, H. Redl, M. van
Griensven, and C. Gabriel, "Human Mesenchymal Stem Cells from
Adipose Tissue and Amnion Influence T-Cells Depending on
Stimulation Method and Presence of Other Immune Cells”, Stem Cells
And Development, vol. 20(12), pp. 2115-2126, 2011.
[5] B. Puissant, C. Barreau, P. Bourin, C. Clavel, J. Corre, C. Bousquet, et
al., "Immunomodulatory effect of human adipose tissue-derived adult
stem cells: comparison with bone marrow mesenchymal stem cells”,
British Journal of Haematology, vol. 129, pp. 118–129, 2005.
[6] C. M. Kolf, E. Cho and R. S. Tuan, "Biology of adult mesenchymal
stem cells: regulation of niche, self-renewal and differentiation”, Arthrits
Research & Therapy, vol. 9, pp. 204-214, 2007.
[7] L. B. Buravkova, O. S. Grinakovskaya, E. R. Andreeva, A. P.
Jambalova, M. P. Kozionova, "Characteristics of mesenchymal stromal
cells from human lipoaspirate cultured under reduced oxygen content”,
Cytology, vol. 51(1), pp. 5-12, 2009
[8] W.L. Grayson, F. Zhao, B. Bunnell, and T. Ma, "Hypoxia enhances
proliferation and tissue formation of human mesenchymal stem cells”
Biochem Biophys Res Commun, vol. 358(3), pp. 948-953, 2007.
[9] C. Fehrer, R. Brunauer, G. Laschober, H. Unterluggauer, S. Reitinger, F.
Kloss, et al., "Reduced oxygen tension attenuates differentiation
capacity of human mesenchymal stem cells and prolongs their lifespan”,
Aging Cell, vol. 6(6), pp. 745-757, 2007.
[10] U. Nekanti, S. Dastidar, P. Venugopal, S. Totey, and M. Ta, "Increased
proliferation and analysis of differential gene expression in human
wharton’s jelly-derived mesenchymal stromal cells under hypoxia” Cell,
vol. 6(5), pp. 499-512, 2010.
[11] J. A. Krieger., J. C. Landsiedel, and D. A. Lawrence, "Differential in
vitro effects of physiological and atmospheric oxygen tension on normal
human peripheral blood mononuclear cell proliferation, cytokine and
immunoglobulin production”. Int. J. Immunopharmacol, vol. 8(10), pp.
545-552, 1996.
[12] C. C. Caldwell, H. Kojima, D. Lukashev, J. Armstrong, M. Farber, S. G.
Apasov, and M. V. Sitkovsky, "Differential Effects of Physiologically
Relevant Hypoxic Conditions on T Lymphocyte Development and
Effector Functions”, The Journal of Immunology, vol. 167, pp. 6140–
6149, 2001.
[13] L. Da Silva Meirelles, T. T. Sand, R. J. Harman, D. P. Lennon and A. I.
Caplan, "MSC frequency correlates with blood vessel density in equine
adipose tissue”, Tissue Eng Part A, vol. 15(2), pp. 221-229, 2009.
[14] Z. Li, H. Wei, L. Deng, X. Cong and X. Chen, "Expression and
secretion of interleukin 1-beta, tumour necrosis factor alpha and
interleukin 10 by hypoxia and serum deprivation-stimulated
mesenchymal stem cells”, FEBS J, vol. 277(18), pp. 3688-3698, 2010.
[15] P. A. Zuk, M. Zhu, H. Mizuno, J. Huang, J. W. Futrell, A. J. Katz, et al.,
"Multilineage cells from human adipose tissue: implications for cellbased
therapies”, Tissue Eng, vol. 7, pp. 211-218, 2001.
[16] K. Le Blanc, I. Rasmusson, C. Gotherstrom, C. Seidel, B. Sundberg, M.
Sundin, et al., "Mesenchymal stem cells inhibit the expression of CD25
(Interleukin-2 Receptor) and CD38 on phytohaemagglutinin-activated
lymphocytes”, Scandinavian Journal of Immunology, vol. 60, pp. 307–
315, 2004.
[17] S Cappellesso-Fleury, B. Puissant, P. A. Apoil, M. Titeux, P. Winterton,
L. Casteilla, P. Bourin and A. Blancher, "Human fibroblasts share
immunosuppressive properties with bone marrow mesenchymal stem
cells”, J Clin Immunol, vol. 30, pp. 607–619, 2010.
[18] W Deng, Q. Han, L. Liao, S. You, H. Deng and R. C. Zhao, "Effects of
allogeneic bone marrow-derived mesenchymal stem cells on T and B
lymphocytes from BXSB mice”, DNA And Cell Biology, vol. 24(7), pp.
458–463, 2005.
[19] F. Saldanha-Araujo, R. Haddad, K. C. Farias, P. Souza Ade, P. V.
Palma, A. G. Araujo, et al., "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., vol.
16(6), pp. 1232-1244, 2012.
[20] K. Le Blanc, "Mesenchymal stromal cells: Tissue repair and immune
modulation”, Cytotherapy, vol. 8(6), pp. 559-561, 2006.
[21] A. J. Nauta and W. E. Fibbe, "Immunomodulatory properties of
mesenchymal stromal cells”, Blood. vol. 110, pp. 3499-3506, 2007.
[22] G. Siegel, R. Schafer, and F. Dazzi, "The Immunosuppressive Properties
of Mesenchymal Stem Cells”, Transplantation, vol. 87(9), pp. 45-49,
2009.
[23] M. Roemeling-van Rhijn, F. K. Mensah, S. S. Korevaar, M. J. Leijs, G.
J. van Osch, J. N. Ijzermans, et al. "Effects of Hypoxia on the
Immunomodulatory Properties of Adipose Tissue-Derived Mesenchymal
Stem cells”, Front Immunol., vol. 18(4:203), Jul. 2013, doi:
10.3389/fimmu.2013.00203. eCollection 2013.
[24] S. Glennie, I. Soeiro, P. J. Dyson, E. W. Lam and F. Dazzi, "Bone
marrow mesenchymal stem cells induce division arrest anergy of
activated T cells”, Blood, vol. 105, pp. 2821-2827, 2005.
[25] K. Sato, K. Ozaki, I., Oh, A. Meguro, K. Hatanaka, T. Nagai et al.,
"Nitric oxide plays a critical role in suppression of T-cell proliferation
by mesenchymal stem cells”, Blood, vol. 109(1), pp. 228–234, 2007.
[26] S.J. Prasanna, D. Gopalakrishnan, S.R. Shankar and A.B. Vasandan,
"Pro-Inflammatory cytokines, IFNc and TNFa, influence immune
properties of human bone marrow and wharton jelly mesenchymal stem
cells differentially”, PLoS One, vol. 5, Iss. 2. - e9016, 2010.
[27] L. Jarvinen, L. Badri, S. Wettlaufer, T. Ohtsuka, T. J. Standiford, G. B.
Toews, et al., "Lung resident mesenchymal stem cells isolated from
human lung allografts inhibit T cell proliferation via a soluble mediator”,
J Immunol., vol. 181(6), pp. 4389-4396, 2008.
[28] A. U. Engela, C. C. Baan, F. J. Dor, W. Weimar, M. J. Hoogduijn, "On
the interactions between mesenchymal stem cells and regulatory T cells
for immunomodulation in transplantation”, Front Immunol., vol. 3. pp.
126-134, 2012.
[29] A. Naldini and F. Carrar, "Hypoxia modulates cyclin and cytokine
expression and inhibits peripheral mononuclear cell proliferation”, J Cell
Physiol., vol. 181(3), pp. 448-454, 1999.
[30] J. Sun, Y. Zhang, M. Yang, Y. Zhang, Q. Xie, Z. Li, et al. "Hypoxia
induces T-cell apoptosis by inhibiting chemokine C receptor 7
expression: the role of adenosine receptor A(2)”, Cell Mol Immunol.,
vol.7(1), pp. 77-82, 2010.
[31] M. Di Nicola, C. Carlo-Stella, M. Magni, M. Milanesi, P. D, Longoni, P.
Matteucci, et al., "Human bone marrow stromal cells suppress Tlymphocyte
proliferation induced by cellular or nonspecific mitogenic
stimuli”, Blood, vol. 99, pp. 3838-3843, 2002.
[32] Z. Selmani, A. Naji, I. Zidi, B. Favier, E. Gaiffe, L. Obert, 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, vol.
26, pp. 212–222, 2008.
[33] R. Romieu-Mourez, M. Francois, M.N. Boivin., M. Bouchentouf, D. E.
Spaner, J. Galipeau et al. "Cytokine modulation of TLR expression and
activation in mesenchymal stromal cells leads to a proinflammatory
phenotype”, J Immunol., vol. 182, pp. 7963–7973, 2009.
[34] R. S. Waterman., S. L. Tomchuck., S. L. Henkle and A. M. Betancourt,
"A new mesenchymal stem cell (MSC) paradigm: polarization into a
pro-inflammatory MSC1 or an immunosuppressive MSC2 phenotype”
PLoS One, vol. 5(4), - e10088, 2010
[35] Z. Selmani, A. Naji, E. Gaiffe, L. Obert, P. Tiberghien, N. Rouas-Freiss,
et al., "HLA-G is a crucial immunosuppressive molecule secreted by
adult human mesenchymal stem cells”, Transplantation, vol. 15(87), pp.
62-66, 2009.
[36] S. Aggarwal and M. F. Pittenger, "Human mesenchymal stem cells
modulate allogeneic immune cell response”, Blood, vol. 105, pp. 1815-
1822, 2005.