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Effects of transplanted bone-marrow-derived mesenchymal stem cells in animal models of acute hepatitis

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Abstract

Our aim was to evaluate the therapeutic effects of bone-marrow-derived mesenchymal stem cells (BMMSCs) on ConA-induced hepatitis and to elucidate the possible mechanism involved. MSCs were isolated from bone marrow and their characteristics and anti-apoptotic effects on the L02 cell line were analyzed. The effect of intravenous infusion of BMMSCs on liver damage was also tested. Furthermore, the recruitment of donor BMMSCs to the liver of recipient animals and their effects on the activity of intrahepatic natural killer T (NKT) cells were investigated. BMMSCs ameliorated liver damage in a time- and dose-dependent manner. Donor BMMSCs were detected in the livers of recipient animals, suggesting that tissue damage stimulated the migration of BMMSCs. Transplanted BMMSCs also suppressed the activity of intrahepatic NKT cells, not only in the liver but throughout the body. The general infusion of BMMSCS ameliorated immunoregulatory activities by the suppression of intrahepatic NKT cells.

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References

  • Anjos-Afonso F, Siapati EK, Bonnet D (2004) In vivo contribution of murine mesenchymal stem cells into multiple cell-types under minimal damage conditions. J Cell Sci 117:5655–5664

    Article  PubMed  CAS  Google Scholar 

  • Arshad MI, Rauch M, L’helgoualc’h A, Julia V, Leite-de-Moraes MC, Lucas-Clerc C, Piquet-Pellorce C, Samson M (2011) NKT cells are required to induce high IL-33 expression in hepatocytes during ConA-induced acute hepatitis. Eur J Immunol 41:2341–2348

    Article  PubMed  CAS  Google Scholar 

  • Bartholomew A, Sturgeon C, Siatskas M, Ferrer K, McIntosh K, Patil S, Hardy W, Devine S, Ucker D, Deans R, Moseley A, Hoffman R (2002) Mesenchymal stem cells suppress lymphocyte proliferation in vitro and prolong skin graft survival in vivo. Exp Hematol 30:42–48

    Article  PubMed  Google Scholar 

  • Cao Y, Sun Z, Liao L, Meng Y, Han Q, Zhao RC (2005) Human adipose tissue-derived stem cells differentiate into endothelial cells in vitro and improve postnatal neovascularization in vivo. Biochem Biophys Res Commun 332:370–379

    Article  PubMed  CAS  Google Scholar 

  • Chen F, Zhu HH, Zhou LF, Li J, Zhao LY, Wu SS, Wang J, Liu W, Chen Z (2010) Genes related to the very early stage of ConA-induced fulminant hepatitis: a gene-chip-based study in a mouse model. BMC Genomics 11:240

    Article  PubMed  Google Scholar 

  • Choi YS, Jeong JA, Lim DS (2012) Mesenchymal stem cell-mediated immature dendritic cells induce regulatory T cell-based immunosuppressive effect. Immunol Invest 41:214–229

    Article  PubMed  CAS  Google Scholar 

  • Deng W, Han Q, Liao L, Li C, Ge W, Zhao Z, You S, Deng H, Murad F, Zhao RC (2005) Engrafted bone marrow-derived flk-(1+) mesenchymal stem cells regenerate skin tissue. Tissue Eng 11:110–119

    Article  PubMed  CAS  Google Scholar 

  • De Ugarte DA, Alfonso Z, Zuk PA, Elbarbary A, Zhu M, Ashjian P, Benhaim P, Hedrick MH, Fraser JK (2003) Differential expression of stem cell mobilization-associated molecules on multi-lineage cells from adipose tissue and bone marrow. Immunol Lett 89:267–270

    Article  PubMed  Google Scholar 

  • Djouad F, Plence P, Bony C, Tropel P, Apparailly F, Sany J, Noel D, Jorgensen C (2003) Immunosuppressive effect of mesenchymal stem cells favors tumor growth in allogeneic animals. Blood 102:3837–3844

    Article  PubMed  CAS  Google Scholar 

  • Duffield JS, Park KM, Hsiao LL, Kelley VR, Scadden DT, Ichimura T, Bonventre JV (2005) Restoration of tubular epithelial cells during repair of the postischemic kidney occurs independently of bone marrow-derived stem cells. J Clin Invest 115:1743–1755

    Article  PubMed  CAS  Google Scholar 

  • Fang B, Shi M, Liao L, Yang S, Liu Y, Zhao RC (2004) Systemic infusion of FLK1(+) mesenchymal stem cells ameliorate carbon tetrachloride-induced liver fibrosis in mice. Transplantation 78:83–88

    Article  PubMed  CAS  Google Scholar 

  • Francois S, Bensidhoum M, Mouiseddine M, Mazurier C, Allenet B, Semont A, Frick J, Sache A, Bouchet S, Thierry D, Gourmelon P, Gorin NC, Chapel A (2006) Local irradiation not only induces homing of human mesenchymal stem cells at exposed sites but promotes their widespread engraftment to multiple organs: a study of their quantitative distribution after irradiation damage. Stem Cells 24:1020–1029

    Article  PubMed  Google Scholar 

  • Gnecchi M, He H, Liang OD, Melo LG, Morello F, Mu H, Noiseux N, Zhang L, Pratt RE, Ingwall JS, Dzau VJ (2005) Paracrine action accounts for marked protection of ischemic heart by Akt-modified mesenchymal stem cells. Nat Med 11:367–368

    Article  PubMed  CAS  Google Scholar 

  • Herrera MB, Bussolati B, Bruno S, Fonsato V, Romanazzi GM, Camussi G (2004) Mesenchymal stem cells contribute to the renal repair of acute tubular epithelial injury. Int J Mol Med 14:1035–1041

    PubMed  Google Scholar 

  • Johann PD, Vaegler M, Gieseke F, Mang P, Armeanu-Ebinger S, Kluba T, Handgretinger R, Müller I (2010) Tumour stromal cells derived from paediatric malignancies display MSC-like properties and impair NK cell cytotoxicity. BMC Cancer 10:501

    Article  PubMed  Google Scholar 

  • 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 101:3722–3729

    Article  PubMed  CAS  Google Scholar 

  • Makohon NV, Pavlovych SI, Bryzhina TM, Aleksiuk LI, Sukhina VS, Hrushka NH, Aleksieieva IM (2008) Proliferation and death of liver mononuclear cells in immune lesions induced by concanavalin A and anti-liver antibodies in mice. Fiziol Zh 54:49–57

    PubMed  CAS  Google Scholar 

  • Mangi AA, Noiseux N, Kong D, He H, Rezvani M, Ingwall JS, Dzau VJ (2003) Mesenchymal stem cells modified with Akt prevent remodeling and restore performance of infarcted hearts. Nat Med 9:1195–1201

    Article  PubMed  CAS  Google Scholar 

  • Mizuno H, Zuk PA, Zhu M, Lorenz HP, Benhaim P, Hedrick MH (1999) Myogenic differentiation by human processed lipoaspirate cells. Plast Reconstr Surg 109:199–209

    Google Scholar 

  • Nakagawa H, Akita S, Fukui M, Fujii T, Akino K (2005) Human mesenchymal stem cells successfully improve skin-substitute wound healing. Br J Dermatol 153:29–36

    Article  PubMed  CAS  Google Scholar 

  • Ortiz LA, Gambelli F, McBride C, Gaupp D, Baddoo M, Kaminski N, Phinney DG (2003) Mesenchymal stem cell engraftment in lung is enhanced in response to bleomycin exposure and ameliorates its fibrotic effects. Proc Natl Acad Sci USA 100:8407–8411

    Article  PubMed  CAS  Google Scholar 

  • Pittenger MF, Mackay AM, Beck SC, Jaiswal RK, Douglas R, Mosca JD, Moorman MA, Simonetti DW, Craig S, Marshak DR (1999) Multilineage potential of adult human mesenchymal stem cells. Science 284:143–147

    Article  PubMed  CAS  Google Scholar 

  • Shi G, Zhang Z, Feng D, Xu Y, Lu Y, Wang J, Jiang J, Zhang Z, Li X, Ning G (2010) Selection of reference genes for quantitative real-time reverse transcription-polymerase chain reaction in concanavalin A-induced hepatitis model. Anal Biochem 401:81–90

    Article  PubMed  CAS  Google Scholar 

  • Shi D, Liao L, Zhang B, Liu R, Dou X, Li J, Zhu X, Yu L, Chen D, Zhao RC (2011) Human adipose tissue-derived mesenchymal stem cells facilitate the immunosuppressive effect of cyclosporin A on T lymphocytes through Jagged-1-mediated inhibition of NF-κB signaling. Exp Hematol 39:214–224

    Article  PubMed  CAS  Google Scholar 

  • Sordi V, Malosio ML, Marchesi F, Mercalli A, Melzi R, Giordano T, Belmonte N, Ferrari G, Leone BE, Bertuzzi F, Zerbini G, Allavena P, Bonifacio E, Piemonti L (2005) Bone marrow mesenchymal stem cells express a restricted set of functionally active chemokine receptors capable of promoting migration to pancreatic islets. Blood 106:419–427

    Article  PubMed  CAS  Google Scholar 

  • Takeda K, Hayakawa Y, Van Kaer L, Matsuda H, Yagita H, Okumura K (2000) Critical contribution of liver natural killer T cells to a murine model of hepatitis. Proc Natl Acad Sci USA 97:5498–5503

    Article  PubMed  CAS  Google Scholar 

  • Wada N, Bartold PM, Gronthos S (2011) Human foreskin fibroblasts exert immunomodulatory properties by a different mechanism to bone marrow stromal/stem cells. Stem Cells Dev 20:647–659

    Article  PubMed  CAS  Google Scholar 

  • Weng JY, Du X, Geng SX, Peng YW, Wang Z, Lu ZS, Wu SJ, Luo CW, Guo R, Ling W, Deng CX, Liao PJ, Xiang AP (2011) Mesenchymal stem cell as salvage treatment for refractory chronic GVHD. Bone Marrow Transplant 45:1732–1740

    Article  Google Scholar 

  • Xishan Z, Guangyu A, Yuguang S, Hongmei Z (2011) The research on the immuno-modulatory defect of mesenchymal stem cell from chronic myeloid leukemia patients. J Exp Clin Cancer Res 30:47

    Article  PubMed  Google Scholar 

  • Zappia E, Casazza S, Pedemonte E, Benvenuto F, Bonanni I, Gerdoni E, Giunti D, Ceravolo A, Cazzanti F, Frassoni F, Mancardi G, Uccelli A (2005) Mesenchymal stem cells ameliorate experimental autoimmune encephalomyelitis inducing T-cell anergy. Blood 106:1755–1761

    Article  PubMed  CAS  Google Scholar 

  • Zhang W, Ge W, Li C, You S, Liao L, Han Q, Deng W, Zhao RC (2005) Effects of mesenchymal stem cells on differentiation, maturation, and function of human monocyte-derived dendritic cells. Stem Cells Dev 13):263–271

    Article  CAS  Google Scholar 

  • Zhang B, Liu R, Shi D, Liu X, Chen Y, Dou X, Zhu X, Lu C, Liang W, Liao L, Zenke M, Zhao RC (2009) Mesenchymal stem cells induce mature dendritic cells into a novel Jagged-2-dependent regulatory dendritic cell population. Blood 113:46–57

    Article  PubMed  CAS  Google Scholar 

  • Zhao ZG, Xu W, Sun L, Li WM, Li QB, Zou P (2012) The characteristics and immunoregulatory functions of regulatory dendritic cells induced by mesenchymal stem cells derived from bone marrow of patient with chronic myeloid leukaemia. Eur J Cancer 48:1884–1895

    Article  PubMed  CAS  Google Scholar 

  • Zhu X, Wang L, Zhang B, Li J, Dou X, Zhao RCJ (2011) TGF-beta1-induced PI3K/Akt/NF-kappaB/MMP9 signalling pathway is activated in Philadelphia chromosome-positive chronic myeloid leukaemia hemangioblasts. Biochem 149:405–414

    Article  CAS  Google Scholar 

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Correspondence to Jun Ren.

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Zhu, X., He, B., Zhou, X. et al. Effects of transplanted bone-marrow-derived mesenchymal stem cells in animal models of acute hepatitis. Cell Tissue Res 351, 477–486 (2013). https://doi.org/10.1007/s00441-012-1524-3

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