Dental follicle mesenchymal stem cells regulate responses in sepsis

Year 2020, Volume: 33 Issue: 1, 7 - 16, 31.01.2020

Fethi Gul Deniz Genc Mustafa Kemal Arslantas , Noushin Zıbandeh Leyla Topcu Tunç Akkoc İsmail Cınel

https://doi.org/10.5472/marumj.681996

Abstract

Objective: Sepsis-induced immune alterations are associated with secondary infections and increased risk of death. The use of mesenchymal stem cells (MSCs) has been described as a novel therapeutic strategy. We evaluated the immunomodulatory effects of human dental follicle (DF-MSCs) on lymphocytes of sepsis and septic shock patients.
Materials and Methods: Peripheral blood mononuclear cells (PBMCs) were isolated from venous blood samples of sepsis, septic shock and healthy subjects. PBMCs were co-cultured in the presence and absence of DF-MSCs with or without interferon-gamma (IFN-γ) for 72 hours. CD4+CD25+FoxP3+regulatory T (Treg) cell frequency, lymphocyte proliferation, cytokine levels and apoptosis were evaluated via flow cytometry.
Results: DF-MSCs significantly suppressed proliferation of lymphocytes in sepsis group compared to septic shock group (p<0.005). DF-MSCs remarkably increased Treg ratio in sepsis compared to control group (p<0.05). Reduction of lymphocyte apoptosis in cocultures of DF-MSCs and PBMC was significant in both sepsis and septic shock groups. IFN-γ stimulation of DF-MSCs ameliorated shift in the T-cell subsets from Th2 to Th1 phenotype in septic shock.
Conclusion: Our findings revealed that DF-MSCs have immunoregulatory effects both in sepsis and septic shock, by reducing interleukin-4 (IL-4) and increasing IFN-γ levels. This immunoreactivity regulation may open new therapeutic approaches for septic shock patients.

Keywords

Sepsis, Septic shock, Dental follicle mesenchymal stem cells, Immunomodulation

References

• [1] Singer M, Deutschman CS, Seymour CW, et al. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA 2016; 315:801-10. doi:10.1001/ jama.2016.0287
• [2] Angus DC,  Linde-Zwirble WT,  Lidicker J,  Clermont G,  Carcillo J,  Pinsky MR. Epidemiology of severe sepsis in the United States: analysis of incidence, outcome, and associated costs of care. Crit Care Med 2001; 29:1303-10. doi: 10.1097/00003.246.200107000-00002
• [3] Kumar G, Kumar N, Taneja A, et al. Nationwide trends of severe sepsis in the 21st century (2000-2007). Chest 2011; 140:1223-31. doi: 10.1378/chest.11-0352.
• [4] Kaukonen KM, Bailey M, Suzuki S, Pilcher D, Bellomo R. Mortality related to severe sepsis and septic shock among critically ill patients in Australia and New Zealand, 2000-2012. JAMA 2014;311:1308-16. doi: 10.1001/jama.2014.2637.
• [5] Kurosawa DJS, Osuchowski MF, Valentine C, Kurosawa S, Remick DG. The pathogenesis of sepsis. Annu Rev Pathol 2011; 6: 19-48. doi:10.1146/annurev-pathol-011.110.130327.
• [6] Sundar KM, Sires M. Sepsis-induced immunosuppression: Implications for secondary infections and complications. Indian J Crit Care Med 2013; 17: 162-69. doi: 10.4103/09725229.117054.
• [7] Hotchkiss RS, Monneret G, Payen D. Immunosuppression in sepsis: a novel understanding of the disorder and a new therapeutic approach. Lancet Infect Dis 2013; 13: 260-8. doi: 10.1016/S1473-3099(13)70001-X.
• [8] Pittenger MF, Mackay AM, Beck SC, et al. Multilineage potential of adult human mesenchymal stem cells. Science 1999;284:143-7. doi: 10.1126/science.284.5411.143.
• [9] Huang GTJ, Gronthos S, Shi S. Mesenchymal stem cells derived from dental tissues vs. those from other sources. J Dent Res 2009; 88: 792-806. doi: 10.1177/002.203.4509340867.
• [10] Le Blanc K,  Frassoni F,  Ball L,  et al. Developmental Committee of the European Group for Blood and Marrow Transplantation. Mesenchymal stem cells for treatment of steroid-resistant, severe, acute graft-versus-host disease: a phase II study. Lancet 2008; 371(9624): 1579-86. doi: 10.1016/ S0140-6736(08)60690-X.
• [11] Kovach TK, Dighe AS, Lobo PI, Cui Q. Interactions between MSCs and Immune Cells: Implications for Bone Healing. J Immunol Res 2015; 2015:752510. doi: 10.1155/2015/752510.
• [12] Zhang Q, Shi S, Liu Y, et al. Mesenchymal stem cells derived from human gingiva are capable of ımmunomodulatory functions and ameliorate ınflammation-related tissue destruction in experimental colitis. J Immunol 2009; 15:183:7787-98. doi: 10.4049/jimmunol.0902318.
• [13] Lombardo E, Poll T, DelaRosa O, Dalemans W. Mesenchymal stem cells as a therapeutic tool to treat sepsis. World J Stem Cells 2015; 7: 368-79. doi: 10.4252/wjsc.v7.i2.368
• [14] Boomer JS, To K, Chang KC, et al. Immunosuppression in patients who die of sepsis and multiple organ failure. JAMA 2011; 306: 2594-605. doi: 10.1001/jama.2011.1829.
• [15] Pierdomenico L,  Bonsi L,  Calvitti M,  et al. Multipotent mesenchymal stem cells with ımmunosuppressive activity can be easily ısolated from dental pulp. Transplantation 2005; 80: 836-42. doi: 10.1097/01.tp.000.017.3794.72151.88
• [16] Genç D, Zibandeh N, Nain E, et al. Dental follicle mesenchymal stem cells downregulate th2 mediated ımmune response in asthmatic patients mononuclear cells. Clin Exp Allergy 2018; 48:663-78. doi: 10.1111/cea.13126
• [17] Genç D, Zibandeh N, Nain E, et al. IFN-γ stimulation of dental follicle mesenchymal stem cells modulates immune response of CD4+T lymphocytes in Der p1+ asthmatic patients in vitro. Allergol Immunopathol (Madr) 2019;S0301-0546(19)300047. doi: 10.1016/j.aller.2018.12.005
• [18] Yildirim S, Zibandeh N, Genc D, Ozcan EM, Goker K, Akkoc T. The comparison of the ımmunologic properties of stem cells ısolated from human exfoliated deciduous teeth, dental pulp, and dental follicles. Stem Cells Int 2016; 2016:4682875. doi: 10.1155/2016/4682875
• [19] Scott MJ, Godshall CJ, Cheadle WG. Jaks, STATs, cytokines, and sepsis. Clin Diagn Lab Immunol 2002; 9: 1153-9. doi: 10.1128/CDLI.9.6.1153–1159.2002
• [20] Rittirsch D,  Flierl MA, Ward PA. Harmful molecular mechanisms in sepsis. Nat Rev Immunol 2008; 8: 776-87. doi: 10.1038/nri2402.
• [21] Chong DL, Sriskandan S. Pro-inflammatory mechanisms in sepsis. Contrib Microbiol 2011; 17: 86–107. doi: 10.1159/000324022.
• [22] Leentjens J, Kox M, van der Hoeven JG, Netea MG, Pickkers P. Immunotherapy for the adjunctive treatment of sepsis: from immunosuppression to immunostimulation. Time for a paradigm change? Am J Respir Crit Care Med 2013; 187: 1287-93. doi: 10.1164/rccm.201.301.0036CP.
• [23] Nalos M, Santner-Nanan B, Parnell G, Tang B, McLean AS, Nanan R. Immune effects of interferon gamma in persistent staphylococcal sepsis. Am J Respir Crit Care Med 2012; 185:110-2. doi: 10.1164/ajrccm.185.1.110.
• [24] Sivanathan KN,  Gronthos S,  Rojas-Canales D,  Thierry B, Coates PT. Interferon-gamma modification of mesenchymal stem cells: implications of autologous and allogeneic mesenchymal stem cell therapy in allotransplantation. Stem Cell Rev 2014; 10:351-75. doi: 10.1007/s12015.014.9495-2.
• [25] Morsczeck C,  Völlner F,  Saugspier M,  et al. Comparison of human dental follicle cells (DFCs) and stem cells from human exfoliated deciduous teeth (SHED) after neural differentiation in vitro. Clinical Oral Investig 2010; 14: 43340. doi: 10.1007/s00784.009.0310-4.
• [26] Rey EG,  Anderson P,  González MA,  Rico L,  Büscher D, Delgado M. Human adult stem cells derived from adipose tissue protect against experimental colitis and sepsis. Gut 2009; 58: 929-39. doi: 10.1136/gut.2008.168534.
• [27] Bernardo ME, Fibbe WE. Mesenchymal stromal cells: sensors and switchers of inflammation. Cell Stem Cell 2013; 13:392402. doi: 10.1016/j.stem.2013.09.006.
• [28] Akiyama K, Chen C, Wang D, et al. Mesenchymal-stemcell-induced immunoregulation involves FAS-ligand-/FASmediated T cell apoptosis. Cell Stem Cell 2012; 10:544-55. doi: 10.1016/j.stem.2012.03.007.
• [29] Krampera M, Cosmi L, Angeli R, et al. Role for interferongamma in the immunomodulatory activity of human bone marrow mesenchymal stem cells. Stem Cells 2006; 24:386-98. doi: 10.1634/stemcells.2005-0008
• [30] Prasanna SJ, Gopalakrishnan D, Shankar SR, Vasandan AB. Pro-inflammatory cytokines, IFN gamma and TNF alpha, influence immune properties of human bone marrow and Wharton jelly mesenchymal stem cells differentially. PLoS One 2010; 5:e9016. doi: 10.1371/journal.pone.0009016
• [31] Reinhart K,  Bauer M,  Riedemann NC,  Hartog CS. New approaches to sepsis: molecular diagnostics and biomarkers. Clin Microbiol Rev 2012; 25: 609-34. doi: 10.1128/ CMR.00016-12.
• [32] Osinalde N, Mitxelena J, Sánchez-Quiles V, et al. Nuclear phosphoproteomic screen uncovers ACLY as mediator of IL2-induced proliferation of CD4+ T lymphocytes. Mol Cell Proteomics 2016; 15:2076-92. doi: 10.1074/mcp.M115.057158.
• [33] Surbatovic M, Popovic N, Vojvodic D, et al. Cytokine profile in severe gram-positive and gram-negative abdominal sepsis. Sci Rep 2015; 5:11355. doi: 10.1038/srep11355
• [34] Lang JD, Matute-Bello G. Lymphocytes, apoptosis and sepsis: making the jump from mice to humans. Crit Care 2009; 13:109. doi: 10.1186/cc7144.
• [35] Rimmelé T,  Payen D,  Cantaluppi V, et al. Immune cell phenotype and function in sepsis. Shock 2016; 45:282-91. doi: 10.1097/SHK.000.000.0000000495.
• [36] Wherry EJ. T cell exhaustion. Nat Immunol 2011; 12: 492-9. doi: 10.1038/ni.2035.
• [37] Hotchkiss RS, Monneret G, Payen D. Sepsis-induced immunosuppression: from cellular dysfunctions to immunotherapy. Nat Rev Immunol 2013; 13: 862-74. doi: 10.1038/nri3552.
• [38] Ward PA. Immunosuppression in Sepsis. JAMA 2011; 306:2618-9. doi: 10.1001/jama.2011.1831.
• [39] Schlosser K, Wang JP, Dos Santos C , et al. Effects of mesenchymal stem cell treatment on systemic cytokine levels in a phase 1 dose escalation safety trial of septic shock patients. Crit Care Med 2019;47:918-25. doi: 10.1097/ CCM.000.000.0000003657.
• [40] Wang Y, Tan L, Jin J, et al. Non-cultured dermal-derived mesenchymal cells attenuate sepsis induced by cecal ligation and puncture in mice. Sci Rep 2015; 5: 16973. doi: 10.1038/ srep16973
• [41] Bone RC. Immunologic dissonance: a continuing evolution in our understanding of the systemic inflammatory response syndrome (SIRS) and the multiple organ dysfunction syndrome (MODS). Ann Intern Med 1996; 125:680-7. doi: 10.7326/0003-4819-125-8-199610.150.00009
• [42] Latifi SQ, O’Riordan MA, Levine AD. Interleukin-10 controls the onset of ırreversible septic shock. Infect Immun 2002; 70: 4441-6. doi: 10.1128/iai.70.8.4441-4446.2002