Plasticity of Mesenchymal Stem Cells based on Immune Regulation Network

Plasticity of Mesenchymal Stem Cells based on Immune Regulation Network

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Author(s)

Author(s): Tingting Ren

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DOI: 10.18483/ijSci.2096 18 98 139-147 Volume 8 - May 2019

Abstract

The immunomodulatory function of mesenchymal stem cells has received increasing attention and is widely used in the treatment of clinical immune diseases. The various signal-stimulating molecules during the inflammatory response are essential for the ability of MSCs to exert immunomodulatory effects and determine the fate of immune regulation in MSCs - pro-inflammatory and anti-inflammatory. Such plasticity relies on a regulatory network between immune cells and MSCs that is formed by cytokines, chemokines, and some small molecules. To gain a deeper understanding of the specific mechanisms by which MSCs exert immunomodulatory effects, it is necessary to clarify the factors involved in regulation, the series of cellular signaling pathways triggered by these factors, and the potential links between them. This article is based on these immune regulation networks, combined with the latest research trends, to provide a theoretical basis for better clinical improvement of MSCs treatment.

Keywords

Mesenchymal Stem Cells, Plasticity, Immune Cells, Cytokines, Immune Regulation Network

References

  1. Friedenstein AJ, Chailakhjan RK, Lalykina KS. The development of fibroblast colonies in monolayer cultures of guineapig bone marrow and spleen cells. Cell Tissue Kinet.1970;3(4):393–403.
  2. Pittenger MF, Mackay AM, Beck SC, Jaiswal RK, Douglas R, Mosca JD, Moorman MA, Simonetti DW, Craig S, Marshak DR. Multilineagepotential of adult human mesenchymal stem cells. Science.1999;284(5411):143–147.
  3. Jiang Y, Jahagirdar BN, Reinhardt RL, Schwartz RE, Keene CD, Ortiz-Gonzalez XR,Reyes M, Lenvik T, Lund T, Blackstad M, Du J, Aldrich S, Lisberg A, Low WC, Largaespada DA, Verfaillie CM. Pluripotency of mesenchymal stem cells derived from adult marrow.Nature. 2002; 418(6893): 41–49.
  4. Dominici M, LeBlanc K, Mueller I, Slaper-Cortenbach I, Marini F, Krause D,Deans R, Keating A, Prockop Dj, Horwitz E. Minimal criteria fordefiningmultipotent mesenchymal stromal cells. The InternationalSociety for Cellular Therapy position statement. Cytotherapy.2006;8(4):315-317.
  5. Alvarez R, Lee HL, Hong C, Wang CY. Single CD271 marker isolates mesenchymal stem cellsfrom human dental pulp. Int J Oral Sci. 2015; 7(4): 205-212.
  6. Rose RA, Jiang H, Wang X, Helke S, Tsoporis JN, Gong N, Keating SC, Parker TG,Backx PH, Keating A. Bone marrow-derived mesenchymal stromal cells express cardiac-specific markers, retain the stromal phenotype, and do not become functionalcardiomyocytes in vitro. Stem Cells. 2008; 26(11): 2884–2892.
  7. Qian H, Yang H, Xu W, Yan Y, Chen Q, Zhu W, Cao H, Yin Q, Zhou H, Mao F, Chen Y. Bone marrow mesenchymal stem cells ameliorate rat acute renalfailure by differentiation into renal tubular epithelial-like cells. Int J Mol Med.2008; 22(3): 325–332.
  8. Cho KA, Ju SY, Cho SJ, Jung YJ, Woo SY, Seoh JY, Han HS, Ryu KH. Mesenchymalstem cells showed the highest potential for theregeneration of injured liver tissue compared with other subpopulations of the bonemarrow. Cell Biol Int. 2009; 33(7): 772–777.
  9. HanF, Wang CY, Yang L, Zhan SD, Zhang M, Tian K. Contribution of murine bone marrow mesenchymal stem cells topancreas regeneration after partial pancreatectomy in mice. Cell Biol Int. 2012; 36(9): 823–831.
  10. Robey TE, Saiget MK, Reinecke H, Murry CE. Systemsapproaches to preventing transplanted cell death in cardiac repair.JMol Cell Cardiol. 2008; 45(4): 567-581.
  11. Mastri M, Lin H, Lee T. Enhancing the efficacy of mesenchymalstem cell therapy. World J Stem Cells. 2014; 6(2): 82-93.
  12. Ying Wang, Xiaodong Chen, Wei Cao, Yufang Shi. Plasticity of mesenchymal stem cells in immunomodulation: pathological and therapeutic implication. Nat Immunol. 2014; 15(11): 1009-1016.
  13. Ren G, Zhang L, Zhao X, Xu G, Zhang Y, Roberts AI, Zhao RC, Shi Y. Mesenchymal stem cell-mediated immunosuppression occurs viaconcerted action of chemokines and nitric oxide. Cell Stem Cell. 2008; 2(2): 141–150.
  14. Sudres M, Norol F, Trenado A, Grégoire S, Charlotte F, Levacher B, Lataillade JJ, Bourin P, Holy X, Vernant JP, Klatzmann D, Cohen JL. Bone marrow mesenchymal stem cells suppress lymphocyteproliferation in vitro but fail to prevent graft-versus-host disease in mice. JImmunol.2006; 176(12): 7761–7767.
  15. Di Nicola M, Carlo-Stella C, Magni M, Milanesi M, Longoni PD, Matteucci P, Grisanti S, Gianni AM. Human bone marrow stromal cells suppress T-lymphocyteproliferation induced by cellular or nonspecific mitogenic stimuli. Blood. 2002; 99(10): 3838–3843.
  16. Bartholomew A, Sturgeon C, Siatskas M, Ferrer K, McIntosh K, Patil S, Hardy W,Devine S, Ucker D, Deans R, Moseley A, Hoffman R. Mesenchymal stem cells suppress lymphocyte proliferationin vitro and prolong skin graft survival in vivo. Exp Hematol. 2002; 30(1): 42–48.
  17. Le Blanc K, MougiakakosD. Multipotent mesenchymal stromal cells and theinnate immune system. Nat Rev Immunol. 2012; 12(5): 383–396.
  18. Uccelli A, Moretta L, PistoiaV. Mesenchymal stem cells in health and disease.Nat Rev Immunol. 2008; 8(9): 726–736.
  19. Shi Y, Su J, Roberts AI, Shou P, Rabson AB, Ren G. How mesenchymal stem cells interact with tissue immune responses.Trends Immunol. 2012; 33(3): 136–143.
  20. BernardoME, FibbeWE. Mesenchymal stromal cells: sensors and switchers of inflammation. Cell Stem Cell. 2013; 13(4): 392–402.
  21. Németh K, Leelahavanichkul A, Yuen PS, Mayer B, Parmelee A, Doi K, Robey PG,Leelahavanichkul K, Koller BH, Brown JM, Hu X, Jelinek I, Star RA, Mezey E. Bone marrow stromal cells attenuate sepsis via prostaglandinE(2)-dependent reprogramming of host macrophages to increase their interleukin-10production. Nat Med. 2009; 15(1): 42–49.
  22. Abumaree MH, Al Jumah MA, Kalionis B, Jawdat D, Al Khaldi A, Abomaray FM,Fatani AS, Chamley LW, Knawy BA. Human placental mesenchymal stem cells (pMSCs) play a roleas immune suppressive cells by shifting macrophage differentiation from inflammatoryM1 to anti-inflammatory M2 macrophages. Stem Cell Rev. 2013; 9(5): 620–641.
  23. Li W, Ren G, Huang Y, Su J, Han Y, Li J, Chen X, Cao K, Chen Q, Shou P, Zhang L,Yuan ZR, Roberts AI, Shi S, Le AD, Shi Y. Mesenchymal stem cells: a double-edged sword in regulating immuneresponses. Cell Death Differ. 2012; 19(9): 1505–1513.
  24. Li MO, Flavell RA. Contextual regulation of inflammation: a duet by transforminggrowth factor-β and interleukin-10. Immunity. 2008; 28(4): 468–476.
  25. Ren G, Zhang L, Zhao X, Xu G, Zhang Y, Roberts AI, Zhao RC, Shi Y. Mesenchymal Stem Cell-MediatedImmunosuppression Occurs via ConcertedAction of Chemokines and Nitric Oxide. Cell Stem Cell. 2008; 2(2): 141-150.
  26. Lazzeri E, Romagnani P. CXCR3-binding chemokines: Novelmultifunctional therapeutic targets. Curr. Drug Targets Immune Endocr. Metabol. Disord. 2005; 5(1): 109–118.
  27. Chan JL, Tang KC, Patel AP, Bonilla LM, Pierobon N, Ponzio NM, Rameshwar P. Antigen-presenting property of mesenchymal stem cells occurs during anarrow window at low levels of interferon-γ. Blood. 2006; 107(12): 4817–4824.
  28. Krampera M, Cosmi L, Angeli R, Pasini A, Liotta F, Andreini A, Santarlasci V, Mazzinghi B, Pizzolo G, Vinante F, Romagnani P, Maggi E, Romagnani S, Annunziato F. Role forinterferon-γ in the immunomodulatory activity of human bone marrowmesenchymal stem cells. Stem Cells. 2006; 24(2): 386–398.
  29. Meisel R, Zibert A, Laryea M, Göbel U, Däubener W, Dilloo D. Human bonemarrow stromal cells inhibit allogeneic T-cell responses by indoleamine 2, 3-dioxygenase–mediated tryptophan degradation. Blood. 2004; 103(12):4619–4621.
  30. Ren G, Zhang L, Zhao X, Xu G, Zhang Y, Roberts AI, Zhao RC, Shi Y. Mesenchymal stemcell-mediated immunosuppression occurs via concerted action of chemokinesand nitric oxide. Cell Stem Cell. 2008;2(2):141-150.
  31. Croitoru-Lamoury J, Lamoury FM, Caristo M, Suzuki K, Walker D, Takikawa O,Taylor R, Brew BJ. Interferon-gamma regulates the proliferation and differentiation of mesenchymal stem cells via activation of indoleamine 2,3 dioxygenase (IDO). PLoSOne. 2011;6(2):e14698.
  32. Dorronsoro A, Ferrin I, Salcedo JM, Jakobsson E, Fernandez-Rueda J, Lang V,Sepulveda P, Fechter K, Pennington D, Trigueros C. Human mesenchymal stromal cells modulate T-cell responses throughTNF-a-mediated activation of NF-kB. Eur J Immunol. 2014;44(2):480-488.
  33. Wang L, Zhao Y, Liu Y, Akiyama K, Chen C, Qu C, Jin Y, Shi S. IFN-gamma and TNF-alpha synergistically induce mesenchymal stem cell impairment and tumorigenesisvia NFκB signaling. Stem Cells. 2013;31(7):1383-95.
  34. Usui Y, Okunuki Y, Hattori T, Kezuka T, Keino H, Ebihara N, Sugita S, Usui M, Goto H, Takeuchi M. Functional expression ofB7H1 on retinal pigment epithelial cells.Exp Eye Res.2008;86(1):52–59.
  35. Vigo T, Procaccini C, Ferrara G, Baranzini S, Oksenberg JR, Matarese G, Diaspro A,Kerlero de Rosbo N, Uccelli A. IFN-γ orchestrates mesenchymal stem cellplasticity through the signal transducer andactivator of transcription 1 and 3 and mammaliantarget of rapamycin pathways. J Allergy Clin Immunol. 2017; 139(5): 1667-1676.
  36. Qing Y, Stark GR. Alternative activation of STAT1 and STAT3 in response to interferon-gamma. J Biol Chem. 2004;279(40):41679-41685.
  37. Ramana CV, Gil MP, Schreiber RD, Stark GR. Stat1-dependent and –independentpathways in IFN-gamma-dependent signaling. Trends Immunol.2002;23(2):96-101.
  38. Laplante M, Sabatini DM. mTOR signaling in growth control and disease. Cell. 2012;149(2):274-293.
  39. Dazert E, Hall MN. mTOR signaling in disease. Curr Opin Cell Biol. 2011;23(6):744-755.
  40. Sheng H, Wang Y, Jin Y, Zhang Q, Zhang Y, Wang L, Shen B, Yin S, Liu W, Cui L, Li N. A critical role of IFN-gamma in priming MSC-mediated suppression of T cell proliferation through upregulation of B7-H1. Cell Res. 2008;18(8):846-857.
  41. Ren G, Zhang L, Zhao X, Xu G, Zhang Y, Roberts AI, Zhao RC, Shi Y. Mesenchymal stemcell-mediated immunosuppression occurs via concerted action of chemokinesand nitric oxide. Cell Stem Cell. 2008;2(2):141-150.
  42. Chinnadurai R, Copland IB, Patel SR, Galipeau J. IDO-Independent Suppression of T Cell Effector Function byIFN-γ–Licensed Human Mesenchymal Stromal Cells. J Immunol. 2014; 192(4): 1491-1501.
  43. Meisel R, Zibert A, Laryea M, Göbel U, Däubener W, Dilloo D. Human bone marrow stromal cells inhibit allogeneic T-cell responses by indoleamine 2,3-dioxygenase-mediated tryptophan degradation. Blood. 2004; 103(12):4619–4621.
  44. Hong J, Hueckelhoven A, Wang L, Schmitt A, Wuchter P, Tabarkiewicz J, Kleist C,Bieback K, Ho AD, Schmitt M. Indoleamine 2,3-dioxygenase mediates inhibition of virus-specificCD8(+) T cell proliferation by human mesenchymal stromal cells. Cytotherapy. 2016; 18(5): 621-629.
  45. Li R, Li H, Sun Q, Liu L, Zhang C, Ren X. Indoleamine 2,3-dioxygenase regulates T cell activity throughVav1/Racpathway. Mol Immunol. 2017; 81: 102-107.
  46. Gianchecchi E, Delfino DV, Fierabracci A.Recent insights into the role of thePD-1/PD-L1 pathway in immunological tolerance andautoimmunity.Autoimmun Rev.2013;12(11):1091-1100.
  47. Parry RV, Chemnitz JM, Frauwirth KA,Lanfranco AR, Braunstein I, Kobayashi SV,Linsley PS, Thompson CB, Riley JL. CTLA-4 and PD-1 receptors inhibit T-cellactivation by distinct mechanisms. Mol CellBiol. 2005;25(21):9543-9553.
  48. Francisco LM, Salinas VH, Brown KE, Vanguri VK, Freeman GJ, Kuchroo VK, Sharpe AH.PD-L1 regulates the development,maintenance, and function of inducedregulatory T cells. J Exp Med. 2009;206(13):3015-3029.
  49. Bennett F, Luxenberg D, Ling V,Wang IM, Marquette K, Lowe D, Khan N, Veldman G, Jacobs KA, Valge-Archer VE, Collins M, Carreno BM.Program death-1 engagement upon TCRactivation has distinct effects oncostimulation and cytokine-drivenproliferation: attenuation of ICOS, IL-4, and IL-21, but not CD28, IL-7, and IL-15 responses. JImmunol. 2003;170(2):711-718.
  50. Salama AD, Chitnis T, Imitola J,Ansari MJ, Akiba H, Tushima F, Azuma M, Yagita H,Sayegh MH, Khoury SJ.Critical role of the programmed death-1 (PD-1) pathway in regulation of experimentalautoimmune encephalomyelitis. J Exp Med.2003;198(1):71-78.
  51. Nishimura H, Minato N, Nakano T, Honjo T.Immunological studies on PD-1 deficientmice: implication of PD-1 as a negativeregulator for B cell responses. Int Immunol.1998;10(10):1563-1572.
  52. Fujiwara H, Maeda Y, Kobayashi K, Nishimori H, Matsuoka K, Fujii N, Kondo E, Tanaka T, Chen L, Azuma M, Yagita H, Tanimoto M.Programmed death-1 pathway in host tissuesameliorates Th17/Th1-mediatedexperimental chronic graft-versus-hostdisease. J Immunol. 2014;193(5):2565-2573.
  53. Won TJ, Jung YJ, Kwon SJ, Lee YJ, Lee DI, Min H, Park ES, Joo SS, Hwang KW.Forcedexpression of programmed death-1 gene on Tcell decreased the incidence of type 1diabetes. Arch Pharm Res. 2010;33(11):1825-1833.
  54. Chinnadurai R, Copland IB, Patel SR, Galipeau J.IDO-independent suppression of T celleffector function by IFN-gamma-licensedhuman mesenchymal stromal cells. JImmunol. 2014;192(4):1491-1501.
  55. Ghiotto M, Gauthier L, Serriari N,Pastor S, Truneh A, Nunès JA, Olive D.PD-L1 and PD-L2 differ in their molecularmechanisms of interaction with PD-1. IntImmunol. 2010;22(8):651-660.
  56. Augello A, Tasso R, Negrini SM,Amateis A, Indiveri F, Cancedda R, Pennesi G.Bone marrow mesenchymal progenitor cellsinhibit lymphocyte proliferation by activationof the programmed death 1 pathway. Eur JImmunol. 2005;35(5):1482-1490.
  57. Brunet A, Bonni A, Zigmond MJ,Lin MZ, Juo P, Hu LS, Anderson MJ, Arden KC,Blenis J, Greenberg ME. Aktpromotes cell survival by phosphorylating andinhibiting a Forkhead transcription factor.Cell. 1999;96(6):857-868.
  58. Lin L, Hron JD, Peng SL. Regulation of NF-kappaB, Th activation, and autoinflammationby the forkhead transcription factor Foxo3a.Immunity.2004;21(2):203-213.
  59. Carosella ED, HoWangYin KY, Favier B, LeMaoult J. HLA-G-dependent suppressor cells: Diverse by nature, function, andsignificance. Hum Immunol. 2008;69(11):700–707.
  60. Götherström C, West A, Liden J, Uzunel M, Lahesmaa R, Le Blanc K. Difference in geneexpression between human fetal liver and adult bone marrowmesenchymal stem cells. Haematologica. 2005;90(8):1017–1026.
  61. Chang CJ, Yen ML, Chen YC, Chien CC, Huang HI, Bai CH, Yen BL. Placenta-derivedmultipotent cells exhibit immunosuppressive properties thatare enhanced in the presence of interferon-gamma. StemCells. 2006;24(11):2466–2477.
  62. Teklemariam T, Purandare B, Zhao L, Hantash BM. Inhibition ofDNA methylation enhances HLA-G expression in humanmesenchymal stem cells. Biochem Biophys Res Commun.2014;452(3):753–759.
  63. Lo´ pez AS, Alegre E, LeMaoult J,Carosella E, González A. Regulatory role oftryptophan degradation pathway in HLA-G expression byhuman monocyte-derived dendritic cells. Mol Immunol.2006;43(14):2151–2160.
  64. Alegre E, Rizzo R, Bortolotti D, Fernandez-Landázuri S, Fainardi E, González A. Some basic aspects ofHLA-G biology. J Immunol Res. 2014;2014:657625.
  65. Kanai T, Fujii T, Kozuma S, Yamashita T, Miki A, Kikuchi A, Taketani Y. Soluble HLA-G influencesthe release of cytokines from allogeneic peripheral bloodmononuclear cells in culture. Mol Hum Reprod.2001;7(2):195–200.
  66. Ketroussi F, Giuliani M, Bahri R, Azzarone B, Charpentier B, Durrbach A. Lymphocyte cell-cycle inhibition by HLA-G is mediated by phosphatase SHP-2 and acts on the mTOR pathway. PLoS One. 2011;6(8):e22776.
  67. Własiuk P, Putowski M, Giannopoulos K. PD1/PD1L pathway, HLA-G and T regulatory cells as newmarkers of immunosuppression in cancers. Postepy Hig Med Dosw. 2016; 70(0): 1044-1058.
  68. Smith WL, Garavito RM, DeWitt DL. Prostaglandinendoperoxide H synthases (cyclooxygenases)-1 and -2. J BiolChem. 1996;271(52):33157–33160.
  69. Kleiveland CR, Kassem M, Lea T. Human mesenchymalstem cell proliferation is regulated by PGE2 through differential activation of cAMP-dependent protein kinase isoforms.Exp Cell Res. 2008;314(8):1831–1838.
  70. Aggarwal S, Pittenger MF. Human mesenchymal stem cellsmodulate allogeneic immune cell responses. Blood. 2005;105(4):1815–1822.
  71. Najar M, Raicevic G, Boufker HI,Fayyad Kazan H, De Bruyn C, Meuleman N, Bron D, Toungouz M, Lagneaux L. Mesenchymalstromal cells use PGE2 to modulate activation and proliferation of lymphocyte subsets: Combined comparison ofadipose tissue, Wharton’s Jelly and bone marrow sources.Cell Immunol.2010;264(2):171–179.
  72. Prigione I, Benvenuto F, Bocca P, Battistini L, Uccelli A, Pistoia V. Reciprocalinteractions between human mesenchymal stem cells and γδT cells orinvariant natural killer T cells. Stem Cells. 2009;27(3): 693–702.
  73. Cheon H, Rho YH, Choi SJ, Lee YH, Song GG, Sohn J, Won NH, Ji JD. Prostaglandin E2augments IL-10 signaling and function. J Immunol. 2006;177(2):1092–1100.
  74. Lu LY, Loi F, Nathan K, Lin TH, Pajarinen J, Gibon E, Nabeshima A, Cordova L, Jämsen E, Yao Z, Goodman SB. Pro-inflammatory M1 macrophages promote osteogenesis by mesenchymal stem cells viathe COX-2-Prostaglandin E2 Pathway. J Orthop Res. 2017; 35(11): 2378-2385.
  75. Sheibanie AF, Yen JH, Khayrullina T, Emig F, Zhang M, Tuma R, Ganea D. The proinflammatory effect of prostaglandin E2 in experimentalinflammatory bowel disease is mediated through the IL-23→IL-17 axis. JImmunol. 2007;178(12):8138–8147.
  76. Plumas J, Chaperot L, Richard MJ, Molens JP, Bensa JC, Favrot MC. Mesenchymal stemcells induce apoptosis of activated T cells. Leukemia. 2005;19(9):1597–1604.
  77. Skibinski G. The role of hepatocyte growth factor/c-metinteractions in the immune system. Arch Immunol Ther Exp(Warsz). 2003;51(5):277–282.
  78. Di Nicola M, Carlo-Stella C, Magni M, Milanesi M, Longoni PD, Matteucci P, Grisanti S, Gianni AM. Human bonemarrow stromal cells suppress T-lymphocyte proliferationinduced by cellular or nonspecific mitogenic stimuli. Blood.2002;99(10):3838–3843.
  79. Yen BL, Yen ML, Hsu PJ, Liu KJ, Wang CJ, Bai CH, Sytwu HK. Multipotent humanmesenchymal stromal cells mediate expansion of myeloid-derived suppressor cells via hepatocyte growth factor/c-metand STAT3. Stem Cell Reports.2013;1(2):139–151.
  80. Rutella S, Bonanno G, Procoli A, Mariotti A, de Ritis DG, Curti A, Danese S, Pessina G, Pandolfi S, Natoni F, Di Febo A, Scambia G, Manfredini R, Salati S, Ferrari S,Pierelli L, Leone G, Lemoli RM. Hepatocyte growthfactor favors monocyte differentiation into regulatory interleukin (IL)-10+ +IL-12low/neg accessory cells with dendritic-cell features. Blood. 2006;108(1):218–227.
  81. Chen PM, Liu KJ, Hsu PJ, Wei CF1, Bai CH, Ho LJ, Sytwu HK, Yen BL. Induction of immunomodulatory monocytes by human mesenchymal stem cell-derivedhepatocyte growth factor through ERK1/2. J Leukoc Biol.2014;96(2):295–303.
  82. Mizuno S, Nakamura T. Improvement of sepsis by hepatocyte growth factor, an anti-inflammatory regulator: emerginginsights and therapeutic potential. Gastroenterol Res Pract.2012;2012:909350.
  83. Kamimoto M, Mizuno S, Nakamura T. Reciprocal regulationof IL-6 and IL-10 balance by HGF via recruitment of hemeoxygenase-1 in macrophages for attenuation of liver injury ina mouse model of endotoxemia. Int J Mol Med. 2009;24(2):161–170.
  84. Lee TH, Wisniewski HG, Vilcek J. A novel secretory tumornecrosis factor-inducible protein (TSG-6) is a member of thefamily of hyaluronate binding proteins, closely related to theadhesion receptor CD44. J Cell Biol.1992;116(2):545–557.
  85. Lee RH, Oh JY, Choi H, Bazhanov N. Therapeutic factors secreted bymesenchymal stromal cells and tissue repair. J Cell Biochem.2011;112(11):3073–3078.
  86. Kota DJ, Wiggins LL, Yoon N, Lee RH. TSG-6 produced byhMSCs delays the onset of autoimmune diabetes bysuppressing Th1 development and enhancing tolerogenicity.Diabetes. 2013;62(6):2048–2058.
  87. Um S, Kim HY, Lee JH, Song IS, Seo BM. TSG-6 secreted by mesenchymal stem cells suppresses immunereactions influenced by BMP-2 through p38 and MEKmitogen-activated protein kinase pathway. Cell Tissue Res. 2017; 368(3): 551-561.
  88. Liu L, Song H, Duan H, Chai J, Yang J, Li X, Yu Y, Zhang X, Hu X, Xiao M, Feng R,Yin H, Hu Q, Yang L, Du J, Li T. TSG-6 secreted by human umbilicalcord-MSCsattenuates severe burn-induced excessive inflammation viainhibiting activations ofP38 andJNK signaling. Sci Rep. 2016; 6: 30121.
  89. Dyer DP, Salanga CL, Johns SC, Valdambrini E, Fuster MM, Milner CM, Day AJ, Handel TM. The Anti-inflammatory Protein TSG-6 Regulates ChemokineFunction by Inhibiting Chemokine/GlycosaminoglycanInteractions. J Biol Chem. 2016; 291(24): 12627-12640.
  90. Ng TH, Britton GJ, Hill EV, Verhagen J, Burton BR, Wraith DC. Regulation of adaptiveimmunity; the role of interleukin-10. Front Immunol. 2013;4:129.
  91. Joss A, Akdis M, Faith A, Blaser K, Akdis CA. IL-10 directly acts on T cellsby specifically altering the CD28 co-stimulation pathway. EurJ Immunol.2000;30(6):1683–1690.
  92. Roncarolo M, Gregori S, Battaglia M, Bacchetta R, Fleischhauer K, Levings MK. Interleukin-10-secreting type 1 regulatory T cells in rodents and humans.Immunol Rev. 2006;212:28–50.
  93. Ivanova-Todorova E, Bochev I, Dimitrov R, Belemezova K, Mourdjeva M, Kyurkchiev S, Kinov P, Altankova I, Kyurkchiev D. Conditioned medium from adipose tissue-derived mesenchymalstem cells induces CD4+FOXP3+ cells and increases IL-10secretion. J Biomed Biotechnol. 2012;2012:295167.
  94. Quinn SR, O’Neill LA. The role of microRNAs in the controland mechanism of action of IL-10. Curr Top MicrobiolImmunol. 2014;380:145–155.
  95. Hermankova B, Zajicova A, Javorkova E, Chudickova M, Trosan P, Hajkova M, Krulova M, Holan V. Suppression of IL-10 production by activated B cells via a cellcontact-dependentcyclooxygenase-2 pathway upregulated inIFN-γ-treatedmesenchymal stem cells. Immunobiology. 2016; 221(2): 129-136.
  96. Ma HC, Wang X, Wu MN, Zhao X, Yuan XW, Shi XL. Interleukin-10 Contributes to Therapeutic Effect ofMesenchymal Stem Cells for Acute Liver Failure via SignalTransducer and Activator of Transcription 3 SignalingPathway. Chin Med J. 2016; 129(8): 967-976.
  97. Waterman RS, Tomchuck SL, Henkle SL, Betancourt AM. A new mesenchymal stem cell (MSC) paradigm: polarizationinto a pro-inflammatory MSC1 or an Immunosuppressive MSC2 phenotype. PLos One. 2010; 5(4): e10088.
  98. van den Bosch MW, Palsson-Mcdermott E, Johnson DS,O'Neill LA. LPS induces the degradation of programmed cell deathprotein 4 (PDCD4) to release Twist2, activating c-Maftranscription to promote interleukin-10 production. J BiolChem. 2014;289(33):22980–22990.
  99. Lo Furno D, Graziano AC, Caggia S, Perrotta RE, Tarico MS, Giuffrida R, Cardile V.Decrease ofapoptosis markers during adipogenic differentiation ofmesenchymal stem cells from human adipose tissue. Apoptosis.2013;18(5):578–588.
  100. Lim JY, Im KI, Lee ES, Kim N, Nam YS,Jeon YW, Cho SG. Enhanced immunoregulation ofmesenchymal stem cells by IL-10-producing type 1 regulatory T cellsin collagen-induced arthritis. Sci Rep. 2016; 6: 26851.
  101. Sato K, Ozaki K, Oh I, Meguro A, Hatanaka K, Nagai T, Muroi K, Ozawa K. Nitric oxide plays a critical role in suppression of T-cell proliferation by mesenchymal stem cells. Blood. 2007; 109(1): 228-234
  102. Mattila JT, Thomas AC. Nitric oxide synthase: non-canonicalexpression patterns.Front Immunol. 2014;5:478.
  103. Yan K, Zhang R, Chen L, Chen F, Liu Y, Peng L, Sun H, Huang W, Sun C, Lv B, Li F,Cai Y, Tang Y, Zou Y, Du M, Qin L, Zhang H, Jiang X. Nitric oxide-mediatedimmunosuppressive effect of human amniotic membrane-derived mesenchymal stem cells on the viability and migrationof microglia. Brain Res. 2014;1590:1–9.
  104. Lin CC, Shih CH, Yang YL, Bien MY, Lin CH, Yu MC, Sureshbabu M, Chen BC.Thrombin induces inducible nitric oxide synthase expression via the MAPK, MSK1, and NF-kappaB signaling pathways in alveolar macrophages. Eur J Pharmacol. 2011; 672(1-3): 180-187,.
  105. Nemeth K, Keane-Myers A, Brown JM, Metcalfe DD, Gorham JD, Bundoc VG, Hodges MG, Jelinek I, Madala S, Karpati S, Mezey E. Bone marrowstromal cells use TGF-beta to suppress allergic responses in amouse model of ragweed-induced asthma. Proc Natl Acad SciU S A. 2010;107(12):5652–5657.
  106. Xu C, Yu P, Han X, Du L, Gan J, Wang Y, Shi Y. TGF-β promotes Immune Responses in the Presence of Mesenchymal Stem Cells. J Immunol. 2014; 192(1): 103-109.
  107. Aghajanova L. Leukemia inhibitory factor and humanembryo implantation. Ann N Y Acad Sci. 2004;1034:176–183.
  108. Linker RA, Kruse N, Israel S, Wei T, Seubert S, Hombach A, Holtmann B, Luhder F,Ransohoff RM, Sendtner M, Gold R. Leukemia inhibitoryfactor deficiency modulates the immune response and limitsautoimmune demyelination: a new role for neurotrophiccytokines in neuroinflammation. J Immunol. 2008;180(4):2204–2213.
  109. Banner LR, Patterson PH, Allchorne A, Poole S, Woolf CJ. Leukemiainhibitory factor is an anti-inflammatory and analgesiccytokine. J Neurosci. 1998;18(14):5456–5462.
  110. Nasef A, Zhang YZ, Mazurier C, Bouchet S, Bensidhoum M, Francois S, Gorin NC,Lopez M, Thierry D, Fouillard L, Chapel A. Selected Stro-1-enriched bone marrow stromal cells display a majorsuppressive effect on lymphocyte proliferation. Int J LabHematol. 2009;31(1):9–19.
  111. Wetzler M, Talpaz M, Lowe DG, Baiocchi G, Gutterman JU, Kurzrock R. Constitutiveexpression of leukemia inhibitory factor RNA by humanbone marrow stromal cells and modulation by IL-1, TNF-alpha, and TGF-beta. Exp Hematol. 1991;19(5):347–351.
  112. Najar M, Raicevic G, Boufker HI, Fayyad-Kazan H, De Bruyn C, Meuleman N, Bron D, Toungouz M, Lagneaux L. Adipose-tissue-derived and Wharton’s jelly-derived mesenchymal stromalcells suppress lymphocyte responses by secreting leukemiainhibitory factor. Tissue Eng Part A. 2010;16(11):3537–3546.
  113. Bamberger AM, Jenatschke S, Schulte HM, Löning T, Bamberger MC. Leukemiainhibitory factor (LIF) stimulates the human HLA-Gpromoter in JEG3 choriocarcinoma cells. J Clin EndocrinolMetab. 2000;85(10):3932–3936.
  114. Dallagi A, Girouard J, Hamelin-Morrissette J, Dadzie R, Laurent L, Vaillancourt C,Lafond J, Carrier C, Reyes-Moreno C. Theactivating effect of IFN-γ on monocytes/macrophages isregulated by the LIF-trophoblast-IL-10 axis via Stat1inhibition and Stat3 activation. Cell Mol Immunol. 2015;12(2):326–341.
  115. Striz I, Brabcova E, Kolesar L, Sekerkova A. Cytokine networking ofinnate immunitycells: a potential target of therapy. Clin Sci(Lond). 2014;126(9):593–612.

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International Journal of Sciences is Open Access Journal.
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Volume 12, June 2023


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