Mesenchymal stem cells induce expansion of regulatory T cells in abortion-prone mice

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  • 1 Department of Immunology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
  • 2 Department of Immunology, School of Medicine, Semnan University of Medical Sciences, Semnan, Iran
  • 3 Department of Immunology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
  • 4 Reproductive Biotechnology Research Center, Avicenna Research Institute, ACECR, Tehran, Iran

Correspondence should be addressed to S M Moazzeni; Email: Moazzeni@modares.ac.ir
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Recurrent pregnancy loss (RPL) is one of the most common complications of early pregnancy associated in most cases with local or systemic immune abnormalities such as the diminished proportion of regulatory T cells (Tregs). Mesenchymal stem cells (MSCs) have been shown to modulate the immune responses by de novo induction and expansion of Tregs. In this study, we analyzed the molecular and cellular mechanisms involved in Treg-associated pregnancy protection following MSCs administration in an abortion-prone mouse mating. In a case-control study, syngeneic abdominal fat-derived MSCs were administered intraperitoneally (i.p) to the DBA/2-mated CBA/J female mice on day 4.5 of pregnancy. Abortion rate, Tregs proportion in spleen and inguinal lymph nodes, Ho1, Foxp3, Pd1 and Ctla4 genes expression at the feto–maternal interface were then measured on day 13.5 of pregnancy using flow cytometry and quantitative RT-PCR, respectively. The abortion rate in MSCs-treated mice reduced significantly and normalized to the level observed in normal pregnant animals. We demonstrated a significant induction of Tregs in inguinal lymph nodes but not in the spleen following MSCs administration. Administration of MSCs remarkably upregulated the expression of Ho1, Foxp3, Pd1 and Ctla4 genes in both placenta and decidua. Here, we show that MSCs therapy could protect the fetus in the abortion-prone mice through Tregs expansion and upregulation of Treg-related genes. These events could establish an immune-privileged microenvironment, which participates in the regulation of detrimental maternal immune responses against the semi-allogeneic fetus.

 

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  • Aggarwal S & Pittenger MF 2005 Human mesenchymal stem cells modulate allogeneic immune cell responses. Blood 105 18151822. (https://doi.org/10.1182/blood-2004-04-1559)

    • Search Google Scholar
    • Export Citation
  • Ahmadabad HN, Salehnia M, Saito S & Moazzeni SM 2016 Decidual soluble factors, through modulation of dendritic cells functions, determine the immune response patterns at the feto-maternal interface. Journal of Reproductive Immunology 114 1017. (https://doi.org/10.1016/j.jri.2016.01.001)

    • Search Google Scholar
    • Export Citation
  • Aluvihare VR, Kallikourdis M & Betz AG 2004 Regulatory T cells mediate maternal tolerance to the fetus. Nature Immunology 5 266271. (https://doi.org/10.1038/ni1037)

    • Search Google Scholar
    • Export Citation
  • Andersen MH, Sørensen RB, Brimnes MK, Svane IM, Becker JC & Straten Pt 2009 Identification of heme oxygenase-1-specific regulatory CD8+ T cells in cancer patients. Journal of Clinical Investigation 119 22452256. (https://doi.org/10.1172/jci38739)

    • Search Google Scholar
    • Export Citation
  • Azimi M, Aslani S, Mortezagholi S, Salek A, Javan MR, Rezaiemanesh A, Ghaedi M, Gholamzad M & Salehi E 2016 Identification, isolation, and functional assay of regulatory T cells. Immunological Investigations 45 584602. (https://doi.org/10.1080/08820139.2016.1193869)

    • Search Google Scholar
    • Export Citation
  • Birebent B, Lorho R, Lechartier H, de Guibert S, Alizadeh M, Vu N, Beauplet A, Robillard N & Semana G 2004 Suppressive properties of human CD4+ CD25+ regulatory T cells are dependent on CTLA‐4 expression. European Journal of Immunology 34 34853496. (https://doi.org/10.1002/eji.200324632)

    • Search Google Scholar
    • Export Citation
  • Bizargity P & Bonney EA 2009 Dendritic cells: a family portrait at mid‐gestation. Immunology 126 565578. (https://doi.org/10.1111/j.1365-2567.2008.02918.x)

    • Search Google Scholar
    • Export Citation
  • Busse M, Campe K-NJ, Nowak D, Schumacher A, Plenagl S, Langwisch S, Tiegs G, Reinhold A & Zenclussen AC 2019 IL-10 producing B cells rescue mouse fetuses from inflammation-driven fetal death and are able to modulate T cell immune responses. Scientific Reports 9 9335. (https://doi.org/10.1038/s41598-019-45860-2)

    • Search Google Scholar
    • Export Citation
  • Carreno BM & Collins M 2002 The B7 family of ligands and its receptors: new pathways for costimulation and inhibition of immune responses. Annual Review of Immunology 20 2953. (https://doi.org/10.1146/annurev.immunol.20.091101.091806)

    • Search Google Scholar
    • Export Citation
  • Carrion F, Nova E, Ruiz C, Diaz F, Inostroza C, Rojo D, Mönckeberg G & Figueroa FE 2010 Autologous mesenchymal stem cell treatment increased T regulatory cells with no effect on disease activity in two systemic lupus erythematosus patients. Lupus 19 317322. (https://doi.org/10.1177/0961203309348983)

    • Search Google Scholar
    • Export Citation
  • Chamberlain G, Fox J, Ashton B & Middleton J 2007 Concise review: mesenchymal stem cells: their phenotype, differentiation capacity, immunological features, and potential for homing. Stem Cells 25 27392749. (https://doi.org/10.1634/stemcells.2007-0197)

    • Search Google Scholar
    • Export Citation
  • Choi BM, Pae HO, Jeong YR, Kim YM & Chung HT 2005 Critical role of heme oxygenase-1 in Foxp3-mediated immune suppression. Biochemical and Biophysical Research Communications 327 10661071. (https://doi.org/10.1016/j.bbrc.2004.12.106)

    • Search Google Scholar
    • Export Citation
  • Daniel D, Chiu C, Giraudo E, Inoue M, Mizzen LA, Chu NR & Hanahan D 2005 CD4+ T cell-mediated antigen-specific immunotherapy in a mouse model of cervical cancer. Cancer Research 65 20182025. (https://doi.org/10.1158/0008-5472.CAN-04-3444)

    • Search Google Scholar
    • Export Citation
  • Djouad F, Charbonnier LM, Bouffi C, Louis‐Plence P, Bony C, Apparailly F, Cantos C, Jorgensen C & Noel D 2007 Mesenchymal stem cells inhibit the differentiation of dendritic cells through an interleukin‐6‐dependent mechanism. Stem Cells 25 20252032. (https://doi.org/10.1634/stemcells.2006-0548)

    • Search Google Scholar
    • Export Citation
  • English K, Barry FP, Field-Corbett CP & Mahon BP 2007 IFN-γ and TNF-α differentially regulate immunomodulation by murine mesenchymal stem cells. Immunology Letters 110 91100. (https://doi.org/10.1016/j.imlet.2007.04.001)

    • Search Google Scholar
    • Export Citation
  • English K, Ryan JM, Tobin L, Murphy MJ, Barry FP & Mahon BP 2009 Cell contact, prostaglandin E2 and transforming growth factor beta 1 play non‐redundant roles in human mesenchymal stem cell induction of CD4+ CD25 high forkhead box P3+ regulatory T cells. Clinical and Experimental Immunology 156 149160. (https://doi.org/10.1111/j.1365-2249.2009.03874.x)

    • Search Google Scholar
    • Export Citation
  • Erlebacher A 2001 Why isn’t the fetus rejected? Current Opinion in Immunology 13 590593. (https://doi.org/10.1016/s0952-7915(0000264-8)

    • Search Google Scholar
    • Export Citation
  • Erlebacher A 2013 Immunology of the maternal-fetal interface. Annual Review of Immunology 31 387411. (https://doi.org/10.1146/annurev-immunol-032712-100003)

    • Search Google Scholar
    • Export Citation
  • Eskandarian M & Moazzeni SM 2019 Uterine dendritic cells modulation by mesenchymal stem cells provides A protective microenvironment at the feto-maternal interface: improved pregnancy outcome in abortion-prone mice. Cell Journal 21 274–280. (https://doi.org/10.22074/cellj.2019.6239)

    • Search Google Scholar
    • Export Citation
  • Fontenot JD & Rudensky AY 2005 A well adapted regulatory contrivance: regulatory T cell development and the forkhead family transcription factor Foxp3. Nature Immunology 6 331337. (https://doi.org/10.1038/ni1179)

    • Search Google Scholar
    • Export Citation
  • Fontenot JD, Gavin MA & Rudensky AY 2003 Foxp3 programs the development and function of CD4+ CD25+ regulatory T cells. Nature Immunology 4 330336. (https://doi.org/10.1038/ni904)

    • Search Google Scholar
    • Export Citation
  • Freeman GJ, Long AJ, Iwai Y, Bourque K, Chernova T, Nishimura H, Fitz LJ, Malenkovich N, Okazaki T & Byrne MC et al. 2000 Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation. Journal of Experimental Medicine 192 10271034. (https://doi.org/10.1084/jem.192.7.1027)

    • Search Google Scholar
    • Export Citation
  • Ghannam S, Pène J, Torcy-Moquet G, Jorgensen C & Yssel H 2010 Mesenchymal stem cells inhibit human Th17 cell differentiation and function and induce a T regulatory cell phenotype. Journal of Immunology 185 302312. (https://doi.org/10.4049/jimmunol.0902007)

    • Search Google Scholar
    • Export Citation
  • Ghionzoli M, Cananzi M, Zani A, Rossi CA, Leon FF, Pierro A, Eaton S & De Coppi P 2010 Amniotic fluid stem cell migration after intraperitoneal injection in pup rats: implication for therapy. Pediatric Surgery International 26 7984. (https://doi.org/10.1007/s00383-009-2504-x)

    • Search Google Scholar
    • Export Citation
  • Gonzalez-Rey E, Anderson P, González MA, Rico L, Büscher D & Delgado M 2009 Human adult stem cells derived from adipose tissue protect against experimental colitis and sepsis. Gut 58 929939. (https://doi.org/10.1136/gut.2008.168534)

    • Search Google Scholar
    • Export Citation
  • Guerin LR, Prins JR & Robertson SA 2009 Regulatory T-cells and immune tolerance in pregnancy: a new target for infertility treatment? Human Reproduction Update 15 517535. (https://doi.org/10.1093/humupd/dmp004)

    • Search Google Scholar
    • Export Citation
  • Habicht A, Dada S, Jurewicz M, Fife BT, Yagita H, Azuma M, Sayegh MH & Guleria I 2007 A link between PDL1 and T regulatory cells in fetomaternal tolerance. Journal of Immunology 179 52115219. (https://doi.org/10.4049/jimmunol.179.8.5211)

    • Search Google Scholar
    • Export Citation
  • Hori S, Nomura T & Sakaguchi S 2003 Control of regulatory T cell development by the transcription factor Foxp3. Science 299 10571061. (https://doi.org/10.1126/science.1079490)

    • Search Google Scholar
    • Export Citation
  • Jasper MJ, Tremellen KP & Robertson SA 2006 Primary unexplained infertility is associated with reduced expression of the T-regulatory cell transcription factor Foxp3 in endometrial tissue. Molecular Human Reproduction 12 301308. (https://doi.org/10.1093/molehr/gal032)

    • Search Google Scholar
    • Export Citation
  • Joffre O, Santolaria T, Calise D, Saati TAl, Hudrisier D, Romagnoli P & Van Meerwijk JP 2008 Prevention of acute and chronic allograft rejection with CD4+ CD25+ Foxp3+ regulatory T lymphocytes. Nature Medicine 14 88–92. (https://doi.org/10.1038/nm1688)

    • Search Google Scholar
    • Export Citation
  • Kean TJ, Lin P, Caplan AI & Dennis JE 2013 MSCs: delivery routes and engraftment, cell-targeting strategies, and immune modulation. Stem Cells International 2013 732742. (https://doi.org/10.1155/2013/732742)

    • Search Google Scholar
    • Export Citation
  • Kidd S, Spaeth E, Dembinski JL, Dietrich M, Watson K, Klopp A, Battula VL, Weil M, Andreeff M & Marini FC 2009 Direct evidence of mesenchymal stem cell tropism for tumor and wounding microenvironments using in vivo bioluminescent imaging. Stem Cells 27 26142623. (https://doi.org/10.1002/stem.187)

    • Search Google Scholar
    • Export Citation
  • Kovach TK, Dighe AS, Lobo PI & Cui Q 2015 Interactions between MSCs and immune cells: implications for bone healing. Journal of Immunology Research 2015 752510. (https://doi.org/10.1155/2015/752510)

    • Search Google Scholar
    • Export Citation
  • Krampera M, Glennie S, Dyson J, Scott D, Laylor R, Simpson E & Dazzi F 2003 Bone marrow mesenchymal stem cells inhibit the response of naive and memory antigen-specific T cells to their cognate peptide. Blood 101 37223729. (https://doi.org/10.1182/blood-2002-07-2104)

    • Search Google Scholar
    • Export Citation
  • La Rocca C, Carbone F, Longobardi S & Matarese G 2014 The immunology of pregnancy: regulatory T cells control maternal immune tolerance toward the fetus. Immunology Letters 162 4148. (https://doi.org/10.1016/j.imlet.2014.06.013)

    • Search Google Scholar
    • Export Citation
  • Leibacher J & Henschler R 2016 Biodistribution, migration and homing of systemically applied mesenchymal stem/stromal cells. Stem Cell Research and Therapy 7 7. (https://doi.org/10.1186/s13287-015-0271-2)

    • Search Google Scholar
    • Export Citation
  • Li W, Li B, Fan W, Geng L, Li X, Li L, Huang Z & Li S 2009 CTLA4Ig gene transfer alleviates abortion in mice by expanding CD4+ CD25+ regulatory T cells and inducing indoleamine 2,3-dioxygenase. Journal of Reproductive Immunology 80 111. (https://doi.org/10.1016/j.jri.2008.11.006)

    • Search Google Scholar
    • Export Citation
  • Luz-Crawford P, Kurte M, Bravo-Alegría J, Contreras R, Nova-Lamperti E, Tejedor G, Noël D, Jorgensen C, Figueroa F & Djouad F et al. 2013 Mesenchymal stem cells generate a CD4+ CD25+ Foxp3+ regulatory T cell population during the differentiation process of Th1 and Th17 cells. Stem Cell Research and Therapy 4 65. (https://doi.org/10.1186/scrt216)

    • Search Google Scholar
    • Export Citation
  • Maccario R, Podestà M, Moretta A, Cometa A, Comoli P, Montagna D, Daudt L, Ibatici A, Piaggio G & Pozzi S 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. Haematologica 90 516525.

    • Search Google Scholar
    • Export Citation
  • Martínez-Varea A, Pellicer B, Perales-Marín A & Pellicer A 2014 Relationship between maternal immunological response during pregnancy and onset of preeclampsia. Journal of Immunology Research 2014 210241. (https://doi.org/10.1155/2014/210241)

    • Search Google Scholar
    • Export Citation
  • McFarlin K, Gao X, Liu YB, Dulchavsky DS, Kwon D, Arbab AS, Bansal M, Li Y, Chopp M & Dulchavsky SA et al. 2006 Bone marrow‐derived mesenchymal stromal cells accelerate wound healing in the rat. Wound Repair and Regeneration 14 471478. (https://doi.org/10.1111/j.1743-6109.2006.00153.x)

    • Search Google Scholar
    • Export Citation
  • Medawar PB 1953 Some immunological and endo-crinological problems raised by the evolution of viviparity in vertebrates. Symposia of the Society for Experimental Biology 7 320337.

    • Search Google Scholar
    • Export Citation
  • Mellor AL & Munn DH 2001 Extinguishing maternal immune responses during pregnancy: implications for immunosuppression. Seminars in Immunology 13 213218. (https://doi.org/10.1006/smim.2000.0317)

    • Search Google Scholar
    • Export Citation
  • Mor G, Cardenas I, Abrahams V & Guller S 2011 Inflammation and pregnancy: the role of the immune system at the implantation site. Annals of the New York Academy of Sciences 1221 8087. (https://doi.org/10.1111/j.1749-6632.2010.05938.x)

    • Search Google Scholar
    • Export Citation
  • Morelli SS, Mandal M, Goldsmith LT, Kashani BN & Ponzio NM 2015 The maternal immune system during pregnancy and its influence on fetal development. Research and Reports in Biology 6 171189. (https://doi.org/10.2147/RRB.S80652)

    • Search Google Scholar
    • Export Citation
  • Norton MT, Fortner KA, Oppenheimer KH & Bonney EA 2010 Evidence that CD8 T‐cell homeostasis and function remain intact during murine pregnancy. Immunology 131 426437. (https://doi.org/10.1111/j.1365-2567.2010.03316.x)

    • Search Google Scholar
    • Export Citation
  • Pae HO, Oh GS, Choi BM, Chae SC & Chung HT 2003 Differential expressions of heme oxygenase-1 gene in CD25− and CD25+ subsets of human CD4+ T cells. Biochemical and Biophysical Research Communications 306 701705. (https://doi.org/10.1016/s0006-291x(0301037-4)

    • Search Google Scholar
    • Export Citation
  • Perico N, Casiraghi F, Introna M, Gotti E, Todeschini M, Cavinato RA, Capelli C, Rambaldi A, Cassis P & Rizzo P et al. 2011 Autologous mesenchymal stromal cells and kidney transplantation: a pilot study of safety and clinical feasibility. Clinical Journal of the American Society of Nephrology 6 412422. (https://doi.org/10.2215/CJN.04950610)

    • Search Google Scholar
    • Export Citation
  • Ren G, Zhang L, Zhao X, Xu G, Zhang Y, Roberts AI, Zhao RC & Shi Y 2008 Mesenchymal stem cell-mediated immunosuppression occurs via concerted action of chemokines and nitric oxide. Cell Stem Cell 2 141150. (https://doi.org/10.1016/j.stem.2007.11.014)

    • Search Google Scholar
    • Export Citation
  • Rezaei F & Moazzeni SM 2019 Comparison of the therapeutic effect of syngeneic, allogeneic, and xenogeneic adipose tissue-derived mesenchymal stem cells on abortion rates in a mouse model. Cell Journal 21 92–98. (https://doi.org/10.22074/cellj.2019.5954)

    • Search Google Scholar
    • Export Citation
  • Rezaei Kahmini F, Shahgaldi S & Moazzeni SM 2020 Mesenchymal stem cells alter the frequency and cytokine profile of natural killer cells in abortion-prone mice. Journal of Cellular Physiology 235 72147223. (https://doi.org/10.1002/jcp.29620)

    • Search Google Scholar
    • Export Citation
  • Robertson SA 2010 Immune regulation of conception and embryo implantation – all about quality control? Journal of Reproductive Immunology 85 5157. (https://doi.org/10.1016/j.jri.2010.01.008)

    • Search Google Scholar
    • Export Citation
  • Ruocco MG, Chaouat G, Florez L, Bensussan A & Klatzmann D 2014 Regulatory T-cells in pregnancy: historical perspective, state of the art, and burning questions. Frontiers in Immunology 5 389. (https://doi.org/10.3389/fimmu.2014.00389)

    • Search Google Scholar
    • Export Citation
  • Rustad KC & Gurtner GC 2012 Mesenchymal stem cells home to sites of injury and inflammation. Advances in Wound Care 1 147152. (https://doi.org/10.1089/wound.2011.0314)

    • Search Google Scholar
    • Export Citation
  • Saito S, Sasaki Y & Sakai M 2005 CD4+ CD25high regulatory T cells in human pregnancy. Journal of Reproductive Immunology 65 111120. (https://doi.org/10.1016/j.jri.2005.01.004)

    • Search Google Scholar
    • Export Citation
  • Sakaguchi S, Yamaguchi T, Nomura T & Ono M 2008 Regulatory T cells and immune tolerance. Cell 133 775787. (https://doi.org/10.1016/j.cell.2008.05.009)

    • Search Google Scholar
    • Export Citation
  • Sasaki Y, Sakai M, Miyazaki S, Higuma S, Shiozaki A & Saito S 2004 Decidual and peripheral blood CD4+ CD25+ regulatory T cells in early pregnancy subjects and spontaneous abortion cases. Molecular Human Reproduction 10 347353. (https://doi.org/10.1093/molehr/gah044)

    • Search Google Scholar
    • Export Citation
  • Schena F, Gambini C, Gregorio A, Mosconi M, Reverberi D, Gattorno M, Casazza S, Uccelli A, Moretta L & Martini A et al. 2010 Interferon‐γ-dependent inhibition of B cell activation by bone marrow-derived mesenchymal stem cells in a murine model of systemic lupus erythematosus. Arthritis and Rheumatism 62 27762786. (https://doi.org/10.1002/art.27560)

    • Search Google Scholar
    • Export Citation
  • Selmani Z, Naji A, Zidi I, Favier B, Gaiffe E, Obert L, Borg C, Saas P, Tiberghien P & Rouas‐Freiss N 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+ CD25highFOXP3+ regulatory T cells. Stem Cells 26 212222. (https://doi.org/10.1634/stemcells.2007-0554)

    • Search Google Scholar
    • Export Citation
  • Shima T, Sasaki Y, Itoh M, Nakashima A, Ishii N, Sugamura K & Saito S 2010 Regulatory T cells are necessary for implantation and maintenance of early pregnancy but not late pregnancy in allogeneic mice. Journal of Reproductive Immunology 85 121129. (https://doi.org/10.1016/j.jri.2010.02.006)

    • Search Google Scholar
    • Export Citation
  • Shokri MR, Bozorgmehr M, Ghanavatinejad A, Falak R, Aleahmad M, Kazemnejad S, Shokri F & Zarnani AH 2019 Human menstrual blood-derived stromal/stem cells modulate functional features of natural killer cells. Scientific Reports 9 10007. (https://doi.org/10.1038/s41598-019-46316-3)

    • Search Google Scholar
    • Export Citation
  • Smigiel KS, Srivastava S, Stolley JM & Campbell DJ 2014 Regulatory T‐cell homeostasis: steady‐state maintenance and modulation during inflammation. Immunological Reviews 259 4059. (https://doi.org/10.1111/imr.12170)

    • Search Google Scholar
    • Export Citation
  • Sollwedel A, Bertoja AZ, Zenclussen ML, Gerlof K, Lisewski U, Wafula P, Sawitzki B, Woiciechowsky C, Volk HD & Zenclussen AC 2005 Protection from abortion by heme oxygenase-1 up-regulation is associated with increased levels of Bag-1 and neuropilin-1 at the fetal-maternal interface. Journal of Immunology 175 48754885. (https://doi.org/10.4049/jimmunol.175.8.4875)

    • Search Google Scholar
    • Export Citation
  • Somerset DA, Zheng Y, Kilby MD, Sansom DM & Drayson MT 2004 Normal human pregnancy is associated with an elevation in the immune suppressive CD25+ CD4+ regulatory T-cell subset. Immunology 112 3843. (https://doi.org/10.1111/j.1365-2567.2004.01869.x)

    • Search Google Scholar
    • Export Citation
  • Spaggiari GM, Capobianco A, Abdelrazik H, Becchetti F, Mingari MC & Moretta L 2008 Mesenchymal stem cells inhibit natural killer–cell proliferation, cytotoxicity, and cytokine production: role of indoleamine 2, 3-dioxygenase and prostaglandin E2. Blood 111 13271333. (https://doi.org/10.1182/blood-2007-02-074997)

    • Search Google Scholar
    • Export Citation
  • Svobodova E, Krulova M, Zajicova A, Pokorna K, Prochazkova J, Trosan P & Holan V 2012 The role of mouse mesenchymal stem cells in differentiation of naive T-cells into anti-inflammatory regulatory T-cell or proinflammatory helper T-cell 17 population. Stem Cells and Development 21 901910. (https://doi.org/10.1089/scd.2011.0157)

    • Search Google Scholar
    • Export Citation
  • Trohatou O & Roubelakis MG 2017 Mesenchymal stem/stromal cells in regenerative medicine: past, present, and future. Cellular Reprogramming 19 217224. (https://doi.org/10.1089/cell.2016.0062)

    • Search Google Scholar
    • Export Citation
  • Trowsdale J & Betz AG 2006 Mother’s little helpers: mechanisms of maternal-fetal tolerance. Nature Immunology 7 241246. (https://doi.org/10.1038/ni1317)

    • Search Google Scholar
    • Export Citation
  • Uccelli A, Moretta L & Pistoia V 2008 Mesenchymal stem cells in health and disease. Nature Reviews: Immunology 8 726736. (https://doi.org/10.1038/nri2395)

    • Search Google Scholar
    • Export Citation
  • Vignali DA, Collison LW & Workman CJ 2008 How regulatory T cells work. Nature Reviews: Immunology 8 523–532. (https://doi.org/10.1038/nri2343)

  • von Burg N, Turchinovich G & Finke D 2015 Maintenance of immune homeostasis through ILC/T cell interactions. Frontiers in Immunology 6 416. (https://doi.org/10.3389/fimmu.2015.00416)

    • Search Google Scholar
    • Export Citation
  • Wagner B & Henschler R 2012 Fate of Intravenously Injected Mesenchymal Stem Cells and Significance for Clinical Application, Mesenchymal Stem Cells-Basics and Clinical Application II, pp. 1937. Springer.

    • Search Google Scholar
    • Export Citation
  • Waldmann H, Graca L, Cobbold S, Adams E, Tone M & Tone Y 2004 Regulatory T cells and organ transplantation. Seminars in Immunology 16 119126. (https://doi.org/10.1016/j.smim.2003.12.007)

    • Search Google Scholar
    • Export Citation
  • Wang M, Liang C, Hu H, Zhou L, Xu B, Wang X, Han Y, Nie Y, Jia S & Liang J et al. 2016 Intraperitoneal injection (IP), intravenous injection (IV) or anal injection (AI)? Best way for mesenchymal stem cells transplantation for colitis. Scientific Reports 6 30696. (https://doi.org/10.1038/srep30696)

    • Search Google Scholar
    • Export Citation
  • Wing K & Sakaguchi S 2010 Regulatory T cells exert checks and balances on self tolerance and autoimmunity. Nature Immunology 11 7–13. (https://doi.org/10.1038/ni.1818)

    • Search Google Scholar
    • Export Citation
  • Woidacki K, Popovic M, Metz M, Schumacher A, Linzke N, Teles A, Poirier F, Fest S, Jensen F & Rabinovich GA et al. 2013 Mast cells rescue implantation defects caused by c-kit deficiency. Cell Death and Disease 4 e462e462. (https://doi.org/10.1038/cddis.2012.214)

    • Search Google Scholar
    • Export Citation
  • Woidacki K, Meyer N, Schumacher A, Goldschmidt A, Maurer M & Zenclussen AC 2015 Transfer of regulatory T cells into abortion-prone mice promotes the expansion of uterine mast cells and normalizes early pregnancy angiogenesis. Scientific Reports 5 13938. (https://doi.org/10.1038/srep13938)

    • Search Google Scholar
    • Export Citation
  • Yang H, Qiu L, Chen G, Ye Z, C & Lin Q 2008 Proportional change of CD4+ CD25+ regulatory T cells in decidua and peripheral blood in unexplained recurrent spontaneous abortion patients. Fertility and Sterility 89 656661. (https://doi.org/10.1016/j.fertnstert.2007.03.037)

    • Search Google Scholar
    • Export Citation
  • Zenclussen AC, Lim E, Knoeller S, Knackstedt M, Hertwig K, Hagen E, Klapp BF & Arck PC 2003 Heme oxygenases in pregnancy II: HO‐2 is downregulated in human pathologic pregnancies. American Journal of Reproductive Immunology 50 6676. (https://doi.org/10.1034/j.1600-0897.2003.00047.x)

    • Search Google Scholar
    • Export Citation
  • Zenclussen AC, Gerlof K, Zenclussen ML, Sollwedel A, Bertoja AZ, Ritter T, Kotsch K, Leber J & Volk H-D 2005a Abnormal T-cell reactivity against paternal antigens in spontaneous abortion. American Journal of Pathology 166 811822. (https://doi.org/10.1016/S0002-9440(1062302-4)

    • Search Google Scholar
    • Export Citation
  • Zenclussen AC, Sollwedel A, Bertoja AZ, Gerlof K, Zenclussen ML, Woiciechowsky C & Volk HD 2005b Heme oxygenase as a therapeutic target in immunological pregnancy complications. International Immunopharmacology 5 4151. (https://doi.org/10.1016/j.intimp.2004.09.011)

    • Search Google Scholar
    • Export Citation
  • Zenclussen AC, Gerlof K, Zenclussen ML, Ritschel S, Zambon Bertoja A, Fest S, Hontsu S, Ueha S, Matsushima K & Leber J et al. 2006a Regulatory T cells induce a privileged tolerant microenvironment at the fetal‐maternal interface. European Journal of Immunology 36 8294. (https://doi.org/10.1002/eji.200535428)

    • Search Google Scholar
    • Export Citation
  • Zenclussen ML, Anegon I, Bertoja AZ, Chauveau C, Vogt K, Gerlof K, Sollwedel A, Volk HD, Ritter T & Zenclussen AC 2006b Over-expression of heme oxygenase-1 by adenoviral gene transfer improves pregnancy outcome in a murine model of abortion. Journal of Reproductive Immunology 69 3552. (https://doi.org/10.1016/j.jri.2005.10.001)

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  • Zhao Q, Ren H & Han Z 2016 Mesenchymal stem cells: immunomodulatory capability and clinical potential in immune diseases. Journal of Cellular Immunotherapy 2 320. (https://doi.org/10.1016/j.jocit.2014.12.001)

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