Human adipose‐tissue derived mesenchymal stem cells induce functional de‐novo regulatory T cells with methylated FOXP3 gene DNA

Due to their immunomodulatory properties, mesenchymal stem cells (MSC) are interesting candidates for cellular therapy for autoimmune disorders, graft‐versus‐host disease and allograft rejection. MSC inhibit the proliferation of effector T cells and induce T cells with a regulatory phenotype. So far it is unknown whether human MSC‐induced CD4+CD25+CD127–forkhead box P3 (FoxP3)+ T cells are functional and whether they originate from effector T cells or represent expanded natural regulatory T cells (nTreg). Perirenal adipose‐tissue derived MSC (ASC) obtained from kidney donors induced a 2·1‐fold increase in the percentage of CD25+CD127–FoxP3+ cells within the CD4+ T cell population from allostimulated CD25–/dim cells. Interleukin (IL)‐2 receptor blocking prevented this induction. The ASC‐induced T cells (iTreg) inhibited effector cell proliferation as effectively as nTreg. The vast majority of cells within the iTreg fraction had a methylated FOXP3 gene Treg‐specific demethylated region (TSDR) indicating that they were not of nTreg origin. In conclusion, ASC induce Treg from effector T cells. These iTreg have immunosuppressive capacities comparable to those of nTreg. Their induction is IL‐2 pathway‐dependent. The dual effect of MSC of inhibiting immune cell proliferation while generating de‐novo immunosuppressive cells emphasizes their potential as cellular immunotherapeutic agent.

[1]  W. Weimar,et al.  Interaction between Adipose Tissue-Derived Mesenchymal Stem Cells and Regulatory T-Cells , 2013, Cell transplantation.

[2]  E. Geissler,et al.  Mesenchymal stem cells are short-lived and do not migrate beyond the lungs after intravenous infusion , 2012, Front. Immun..

[3]  N. Perico,et al.  Localization of Mesenchymal Stromal Cells Dictates Their Immune or Proinflammatory Effects in Kidney Transplantation , 2012, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[4]  W. Fibbe,et al.  Safety and efficacy of mesenchymal stromal cell therapy in autoimmune disorders , 2012, Annals of the New York Academy of Sciences.

[5]  J. Lafaille,et al.  Induced CD4+Foxp3+ regulatory T cells in immune tolerance. , 2012, Annual review of immunology.

[6]  J. Allison,et al.  Expression of Helios in Peripherally Induced Foxp3+ Regulatory T Cells , 2012, The Journal of Immunology.

[7]  W. Weimar,et al.  Mesenchymal stem cells: application for solid-organ transplantation , 2012, Current opinion in organ transplantation.

[8]  R. Cancedda,et al.  Mesenchymal stem cells induce functionally active T-regulatory lymphocytes in a paracrine fashion and ameliorate experimental autoimmune uveitis. , 2012, Investigative ophthalmology & visual science.

[9]  C. Ricordi,et al.  Concise Review: Mesenchymal Stem Cells for Diabetes , 2012, Stem cells translational medicine.

[10]  E. Patsouris,et al.  Improvement of skin-graft survival after autologous transplantation of adipose-derived stem cells in rats. , 2011, Journal of plastic, reconstructive & aesthetic surgery : JPRAS.

[11]  B. Levine,et al.  The PDL1-PD1 Axis Converts Human TH1 Cells into Regulatory T Cells , 2011, Science Translational Medicine.

[12]  J. Ritz,et al.  Interleukin-2 and regulatory T cells in graft-versus-host disease. , 2011, The New England journal of medicine.

[13]  U. Beier,et al.  Helios Expression Is a Marker of T Cell Activation and Proliferation , 2011, PloS one.

[14]  R. Negrin,et al.  Rapamycin and IL-2 reduce lethal acute graft-versus-host disease associated with increased expansion of donor type CD4+CD25+Foxp3+ regulatory T cells. , 2011, Blood.

[15]  R. Bronson,et al.  Prevention of type 1 diabetes in mice by tolerogenic vaccination with a strong agonist insulin mimetope , 2011, The Journal of experimental medicine.

[16]  Kazuya Sato,et al.  Mesenchymal stromal cells inhibit Th17 but not regulatory T-cell differentiation. , 2011, Cytotherapy.

[17]  N. Tajiri,et al.  Amniotic Fluid as a Rich Source of Mesenchymal Stromal Cells for Transplantation Therapy , 2011, Cell transplantation.

[18]  M. Kay,et al.  Immunogenicity and Immunomodulatory Properties of Umbilical Cord Lining Mesenchymal Stem Cells , 2011, Cell transplantation.

[19]  D. Mougiakakos,et al.  The impact of inflammatory licensing on heme oxygenase-1-mediated induction of regulatory T cells by human mesenchymal stem cells. , 2011, Blood.

[20]  T. Malek,et al.  T‐cell tolerance and the multi‐functional role of IL‐2R signaling in T‐regulatory cells , 2011, Immunological reviews.

[21]  B. Falini,et al.  Tregs prevent GVHD and promote immune reconstitution in HLA-haploidentical transplantation. , 2011, Blood.

[22]  B. Mahon,et al.  Allogeneic mesenchymal stem cells prevent allergic airway inflammation by inducing murine regulatory T cells , 2011, Allergy.

[23]  N. Perico,et al.  Autologous mesenchymal stromal cells and kidney transplantation: a pilot study of safety and clinical feasibility. , 2011, Clinical journal of the American Society of Nephrology : CJASN.

[24]  J. Wagner,et al.  Infusion of ex vivo expanded T regulatory cells in adults transplanted with umbilical cord blood: safety profile and detection kinetics. , 2011, Blood.

[25]  Hao Wang,et al.  Regulatory T-Cell Generation and Kidney Allograft Tolerance Induced by Mesenchymal Stem Cells Associated With Indoleamine 2,3-Dioxygenase Expression , 2010, Transplantation.

[26]  R. Goto,et al.  Ex Vivo–Expanded Human Regulatory T Cells Prevent the Rejection of Skin Allografts in a Humanized Mouse Model , 2010, Transplantation.

[27]  A. Nicolaou,et al.  The immunomodulatory properties of mesenchymal stem cells and their use for immunotherapy. , 2010, International immunopharmacology.

[28]  W. Weimar,et al.  Inflammatory conditions affect gene expression and function of human adipose tissue‐derived mesenchymal stem cells , 2010, Clinical and experimental immunology.

[29]  C. Jorgensen,et al.  Mesenchymal Stem Cells Inhibit Human Th17 Cell Differentiation and Function and Induce a T Regulatory Cell Phenotype , 2010, The Journal of Immunology.

[30]  K. Wood,et al.  In vivo Prevention of Transplant Arteriosclerosis by ex vivo Expanded Human Regulatory T Cells , 2010, Nature Medicine.

[31]  Y. Belkaid,et al.  Expression of Helios, an Ikaros Transcription Factor Family Member, Differentiates Thymic-Derived from Peripherally Induced Foxp3+ T Regulatory Cells , 2010, The Journal of Immunology.

[32]  W. Weimar,et al.  Characterization of Rabbit Antithymocyte Globulins-Induced CD25+ Regulatory T Cells From Cells of Patients With End-Stage Renal Disease , 2010, Transplantation.

[33]  J. Myśliwska,et al.  First-in-man clinical results of the treatment of patients with graft versus host disease with human ex vivo expanded CD4+CD25+CD127- T regulatory cells. , 2009, Clinical immunology.

[34]  A. Bartholomew,et al.  Infusion of Mesenchymal Stem Cells and Rapamycin Synergize to Attenuate Alloimmune Responses and Promote Cardiac Allograft Tolerance , 2009, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[35]  M. A. Curotto de Lafaille,et al.  Natural and adaptive foxp3+ regulatory T cells: more of the same or a division of labor? , 2009, Immunity.

[36]  W. Weimar,et al.  Donor-Derived Mesenchymal Stem Cells Suppress Alloreactivity of Kidney Transplant Patients , 2009, Transplantation.

[37]  Daniel J. Campbell,et al.  T-bet controls regulatory T cell homeostasis and function during type-1 inflammation , 2009, Nature Immunology.

[38]  Manuel A. González,et al.  Adipose-derived mesenchymal stem cells alleviate experimental colitis by inhibiting inflammatory and autoimmune responses. , 2009, Gastroenterology.

[39]  Fabian Model,et al.  Quantitative DNA methylation analysis of FOXP3 as a new method for counting regulatory T cells in peripheral blood and solid tissue. , 2009, Cancer research.

[40]  J. Ryan,et al.  Cell contact, prostaglandin E2 and transforming growth factor beta 1 play non‐redundant roles in human mesenchymal stem cell induction of CD4+CD25Highforkhead box P3+ regulatory T cells , 2008, Clinical and experimental immunology.

[41]  E. Geissler,et al.  Mesenchymal stem cells can induce long-term acceptance of solid organ allografts in synergy with low-dose mycophenolate. , 2008, Transplant immunology.

[42]  T. Nomura,et al.  CTLA-4 Control over Foxp3+ Regulatory T Cell Function , 2008, Science.

[43]  N. Perico,et al.  Pretransplant Infusion of Mesenchymal Stem Cells Prolongs the Survival of a Semiallogeneic Heart Transplant through the Generation of Regulatory T Cells1 , 2008, The Journal of Immunology.

[44]  G. Dini,et al.  Mesenchymal stem cells for treatment of steroid-resistant, severe, acute graft-versus-host disease: a phase II study , 2008, The Lancet.

[45]  A. Tabilio,et al.  Mesenchymal cells recruit and regulate T regulatory cells. , 2008, Experimental hematology.

[46]  W. Weimar,et al.  Human heart, spleen, and perirenal fat-derived mesenchymal stem cells have immunomodulatory capacities. , 2007, Stem cells and development.

[47]  A. Cope,et al.  The Antiproliferative Effect of Mesenchymal Stem Cells Is a Fundamental Property Shared by All Stromal Cells1 , 2007, The Journal of Immunology.

[48]  I. Türbachova,et al.  DNA demethylation in the human FOXP3 locus discriminates regulatory T cells from activated FOXP3+ conventional T cells , 2007, European journal of immunology.

[49]  M. Haniffa,et al.  Adult Human Fibroblasts Are Potent Immunoregulatory Cells and Functionally Equivalent to Mesenchymal Stem Cells1 , 2007, The Journal of Immunology.

[50]  L. Fouillard,et al.  Immunosuppressive Effects of Mesenchymal Stem Cells: Involvement of HLA-G , 2007, Transplantation.

[51]  T. Nomura,et al.  Foxp3 controls regulatory T-cell function by interacting with AML1/Runx1 , 2007, Nature.

[52]  K. Wood,et al.  GITR Ligation Blocks Allograft Protection by Induced CD25+CD4+ Regulatory T Cells without Enhancing Effector T‐Cell Function , 2007, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[53]  A. Rudensky,et al.  Genome-wide analysis of Foxp3 target genes in developing and mature regulatory T cells , 2007, Nature.

[54]  Ernest Fraenkel,et al.  Foxp3 occupancy and regulation of key target genes during T-cell stimulation , 2007, Nature.

[55]  J. Stroud,et al.  FOXP3 Controls Regulatory T Cell Function through Cooperation with NFAT , 2006, Cell.

[56]  Sergio Romagnani,et al.  Role for Interferon‐γ in the Immunomodulatory Activity of Human Bone Marrow Mesenchymal Stem Cells , 2006 .

[57]  S. Perez,et al.  Interactions Between Human Mesenchymal Stem Cells and Natural Killer Cells , 2006, Stem cells.

[58]  O. Koç,et al.  Human mesenchymal stem cells require monocyte-mediated activation to suppress alloreactive T cells. , 2005, Experimental hematology.

[59]  M. Battaglia,et al.  Rapamycin selectively expands CD4+CD25+FoxP3+ regulatory T cells. , 2005, Blood.

[60]  Yi Zhang,et al.  Human mesenchymal stem cells inhibit differentiation and function of monocyte-derived dendritic cells. , 2005, Blood.

[61]  R. Cancedda,et al.  Bone marrow mesenchymal progenitor cells inhibit lymphocyte proliferation by activation of the programmed death 1 pathway , 2005, European journal of immunology.

[62]  Matthias Edinger,et al.  Only the CD62L+ subpopulation of CD4+CD25+ regulatory T cells protects from lethal acute GVHD. , 2005, Blood.

[63]  M. Pittenger,et al.  Human mesenchymal stem cells modulate allogeneic immune cell responses. , 2005, Blood.

[64]  M. A. Curotto de Lafaille,et al.  CD25− T Cells Generate CD25+Foxp3+ Regulatory T Cells by Peripheral Expansion1 , 2004, The Journal of Immunology.

[65]  Moustapha Hassan,et al.  Treatment of severe acute graft-versus-host disease with third party haploidentical mesenchymal stem cells , 2004, The Lancet.

[66]  Min Zhu,et al.  Human adipose tissue is a source of multipotent stem cells. , 2002, Molecular biology of the cell.

[67]  J. Lafaille,et al.  Interleukin 2 Signaling Is Required for CD4+ Regulatory T Cell Function , 2002, The Journal of experimental medicine.

[68]  C. Carlo-Stella,et al.  Human bone marrow stromal cells suppress T-lymphocyte proliferation induced by cellular or nonspecific mitogenic stimuli. , 2002, Blood.

[69]  Thomas D. Schmittgen,et al.  Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. , 2001, Methods.

[70]  A. Wolffe,et al.  DNA demethylation. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[71]  M. Pittenger,et al.  Multilineage potential of adult human mesenchymal stem cells. , 1999, Science.

[72]  Ludmila Buravkova.  Mesenchymal stromal cells (MSCs) , 2020 .

[73]  T. Board,et al.  Mesenchymal Stem Cells , 2014 .

[74]  F. Carrión,et al.  Mesenchymal stem cell treatment for autoimmune diseases: a critical review. , 2012, Biological research.

[75]  Kazuya Sato,et al.  Nitric oxide plays a critical role in suppression of T-cell proliferation by mesenchymal stem cells. , 2007, Blood.

[76]  F. Benvenuto,et al.  Human mesenchymal stem cells modulate B-cell functions. , 2006, Blood.

[77]  Sergio Romagnani,et al.  Role for interferon-gamma in the immunomodulatory activity of human bone marrow mesenchymal stem cells. , 2006, Stem cells.

[78]  Kevin McIntosh,et al.  Mesenchymal stem cells suppress lymphocyte proliferation in vitro and prolong skin graft survival in vivo. , 2002, Experimental hematology.

[79]  S. Wickramasinghe.  Human bone marrow , 1975 .

[80]  S. Miller,et al.  EncephalomyelitisExperimental Autoimmune System Inflammation During Active Immune Responses and Central Nervous Cells Suppress Antigen-Specific Autoreactive Regulatory T + CD25+ Cutting Edge: CD4 , 2022 .