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Liver regeneration with the resolution of fibrosis by bone marrow cell infusion therapy

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Abstract

Infused (transplanted) green fluorescent protein (GFP)-positive bone marrow cells (BMCs) migrated into the peri-portal regions of the cirrhotic mouse liver induced continuous CCl4 injection without irradiation (without bone marrow ablation). The infused GFP-positive BMCs differentiated into hepatoblasts detected with Liv2-antibody and then differentiated into albumin-producing hepatocytes. The differentiation “niche” induced by persistent liver damage due to continuous CCl4 injection seems to be an essential factor. Microarry analysis showed that at an early stage after BMC infusion through mouse tail vein, the genes related to degradation of extracellular matrix (ECM) e.g. MMP-9 were activated. BMC infusion improved liver fibrosis and the survival rate. Recent our finding indicates that mesencymal bone marrow cells will differentiate to hepatocytes and FGF2 will accelerate this differentiation of BMC to hepatocyte. Based on the results obtained in basic research using the GFP/CCl4 model, human trials are now undergoing.

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References

  • Alison MR, Poulsom R, Jeffery R, Dhillon AP, Quaglia A, Jacob J, Novelli M, Prentice G, Williamson J, Wright NA. (2000) Hepatocytes from non-hepatic adult stem cells. Nature 406:257.

    Article  PubMed  CAS  Google Scholar 

  • Alvarez-Dolado M, Pardal R, Garcia-Verdugo JM, Fike JR, Lee HO, Pfeffer K, Lois C, Morrison SJ, Alvarez-Buylla A. (2003) Fusion of bone-marrow-derived cells with Purkinje neurons, cardiomyocytes and hepatocytes. Nature 425:968–973.

    Article  PubMed  CAS  Google Scholar 

  • Camargo FD, Finegold M, Goodell MA. (2004) Hematopoietic myelomonocytic cells are the major source of hepatocyte fusion partners. J Clin Invest 113:1266–1270.

    Article  PubMed  CAS  Google Scholar 

  • Forbes SJ, Russo FP, Rey V, Burra P, Rugge M, Wright NA, Alison MR. (2004) A significant proportion of myofibroblasts are of bone marrow origin in human liver fibrosis. Gastroenterology 126:955–963.

    Article  PubMed  Google Scholar 

  • Fox IJ, Chowdhury JR, Kaufman SS, Goertzen TC, Chowdhury NR, Warkentin PI, Dorko K, Sauter BV, Strom SC. (1998) Treatment of the Crigler-Najjar syndrome type I with hepatocyte transplantation. N Engl J Med 338:1422–1426.

    Article  PubMed  CAS  Google Scholar 

  • Grisham JW, Thorgeirsson SS. (1997) Liver stem cells. Potten CS eds. Stem Cells. Academic Press London, pp 233–282.

    Google Scholar 

  • Harris RG, Herzog EL, Bruscia EM, Grove JE, Van Arnam JS, Krause DS. (2004) Lack of a fusion requirement for development of bone marrow-derived epithelia. Science 305:90–93.

    Article  PubMed  CAS  Google Scholar 

  • Ianus A, Holz GG, Theise ND, Hussain MA. (2003) In vivo derivation of glucose-competent pancreatic endocrine cells from bone marrow without evidence of cell fusion. J Clin Invest 111:843–850.

    Article  PubMed  CAS  Google Scholar 

  • Ishikawa T, Terai S, Urata Y, Marumoto Y, Aoyama K, Sakaida I, Murata T, Nishina H, Shinoda K, Uchimura S, Hamamoto Y, Okita K. (2005) Fibro-blast growth factor 2 facilitates the differentiation of transplanted bone marrow cells into hepatocytes. Cell Tissue Res. 14:1–11.

    Google Scholar 

  • 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. (2002) Pluripotency of mesenchymal stem cells derived from adult marrow. Nature 418:41–49.

    Article  PubMed  CAS  Google Scholar 

  • Krause DS, Theise ND, Collector MI, Henegariu O, Hwang S, Gardner R, Neutzel S, Sharkis SJ. (2001) Multi-organ, multi-lineage engraftment by a single bone marrow-derived stem cell. Cell 105:369–377.

    Article  PubMed  CAS  Google Scholar 

  • Kobayashi T, Hamano K, Li TS, Nishida M, Ikenaga S, Hirata K, Zempo N, Esato K. (2002) Therapeutic angiogenesis induced by local autologous bone marrow cell implantation. Ann Thorac Surg 73:1210–1215.

    Article  PubMed  Google Scholar 

  • Korbling M, Katz RL, Khanna A, Ruifrok AC, Rondon G, Albitar M, Champlin RE, Estrov Z. (2000) Hepatocytes and epithelial cells of donor origin in recipients of peripheral-blood stem cells. N Engl J Med 346:738–746.

    Article  Google Scholar 

  • Lagasse E, Connors H, Al-Dhalimy M, Reitsma M, Dohse M, Osborne L, Wang X, Finegold M, Weissman IL, Grompe M. (2000) Purified hematopoietic stem cells can differentiate into hepatocytes in vivo. Nat Med 6:1229–1234.

    Article  PubMed  CAS  Google Scholar 

  • Lee KD, Kuo TK, Whang-Peng J, Chung YF, Lin CT, Chou SH, Chen JR, Chen YP, Lee OK. (2004) In vitro hepatic differentiation of human mesenchymal stem cells. Hepatology 40:1275–1284.

    Article  PubMed  CAS  Google Scholar 

  • Muraca M, Gerunda G, Neri D, Vilei MT, Granato A, Feltracco P, Meroni M, Giron G, Burlina AB. (2002) Hepatocyte transplantation as a treatment for glycogen storage disease type la. Lancet 359:317–318.

    Article  PubMed  Google Scholar 

  • Okabe M, Ikawa M, Kominami K, Nakanishi T, Nishimune Y. (1997) “Green mice” as a source of ubiquitous green cells. FEBS Lett 407:313–319.

    Article  PubMed  CAS  Google Scholar 

  • Okamoto R, Yajima T, Yamazaki M, Kanai T, Mukai M, Okamoto S, Ikeda Y, Hibi T, Inazawa J, Watanabe M. (2002) Damaged epithelia regenerated by bone marrow-derived cells in the human gastrointestinal tract. Nat Med 8: 1011–1017.

    Article  PubMed  CAS  Google Scholar 

  • Omori K, Terai S, Ishikawa T, Aoyama K, Sakaida I, Nishina H, Shinoda K, Uchimura S, Hamamoto Y, Okita K. (2004) Molecular signature associated with plasticity of bone marrow cell under persistent liver damage by self-organizing-map-based gene expression. FEBS Lett 578:10–20.

    Article  PubMed  CAS  Google Scholar 

  • Petersen BE, Zajac VF, Michalopoulos GK. (1998) Hepatic oval cell activation in response to injury following chemically induced periportal or pericentral damage in rats. Hepatology 27:1030–1038.

    Article  PubMed  CAS  Google Scholar 

  • Petersen BE, Bowen WC, Patrene KD, Mars WM, Sullivan AK, Murase N, Boggs SS, Greenberger JS, Goff JP. (1999) Bone marrow as a potential source of hepatic oval cells. Science 284:1168–1170.

    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 

  • Sakaida I, Terai S, Yamamoto N, Aoyama K, Ishikawa T, Nishina H, Okita K. (2004) Transplantation of bone marrow cells reduces CCl4-induced liver fibrosis in mice. Hepatology 40:1304–1311.

    Article  PubMed  Google Scholar 

  • Schena M, Shalon D, Davis RW, Brown PO. (1995) Quantitative monitoring of gene expression patterns with a complementary DNA microarray. Science 270:467–470.

    Article  PubMed  CAS  Google Scholar 

  • Shinoda K, Mori S, Ohtsuki T, Osawa Y. (1992) An aromatase-associated cyto-plasmic inclusion, the “stigmoid body,” in the rat brain: I. Distribution in the forebrain. J Comp Neurol 322:360–376.

    Article  PubMed  CAS  Google Scholar 

  • Stamm C, Westphal B, Kleine HD, Petzsch M, Kittner C, Klinge H, Schumichen C, Nienaber CA, Freund M, Steinhoff G. (2003) Autologous bone-marrow stem-cell transplantation for myocardial regeneration. Lancet 361:45–46.

    Article  PubMed  Google Scholar 

  • Tateishi-Yuyama E, Matsubara H, Murohara T, Ikeda U, Shintani S, Masaki H, Amano K, Kishimoto Y, Yoshimoto K, Akashi H, Shimada K, Iwasaka T, Imaizumi T. (2003) Therapeutic Angiogenesis using Cell Transplantation (TACT) Study Investigators. Therapeutic angiogenesis for patients with limb ischaemia by autologous transplantation of bone-marrow cells: a pilot study and a randomised controlled trial. Lancet 360:427–435.

    Article  Google Scholar 

  • Terada N, Hamazaki T, Oka M, Hoki M, Mastalerz DM, Nakano Y, Meyer EM, Morel L, Petersen BE, Scott EW (2002) Bone marrow cells adopt the phenotype of other cells by spontaneous cell fusion. Nature 416:542–545.

    Article  PubMed  CAS  Google Scholar 

  • Terai S, Sakaida I, Yamamoto N, Omori K, Watanabe T, Ohata S, Katada T, Miyamoto K, Shinoda K, Nishina H, Okita K. (2003) An in vivo model for monitoring trans-differentiation of bone marrow cells into functional hepatocytes. J Biochem 134:551–558.

    Article  PubMed  CAS  Google Scholar 

  • Theise ND, Nimmakayalu M, Gardner R, Illei PB, Morgan G, Teperman L, Henegariu O, Krause DS. (2000) Liver from bone marrow in humans. Hepatology 32:11–16.

    Article  PubMed  CAS  Google Scholar 

  • Uchida N, Fujisaki T, Eaves AC, Eaves CJ. (2001) Transplantable hematopoietic stem cells in human fetal liver have a CD34(+) side population (SP)phenotype. J Clin Invest 108:1071–1077.

    Article  PubMed  CAS  Google Scholar 

  • Vassilopoulos G, Wang PR, Russell DW. (2003) Transplanted bone marrow regenerates liver by cell fusion. Nature 422:901–904.

    Article  PubMed  CAS  Google Scholar 

  • Vig P, Russo FP, Edwards RJ, Tadrous PJ, Wright NA, Thomas HC, Alison MR, Forbes SJ. (2006) The sources of parenchymal regeneration after chronic hepatocellular liver injury in mice. Hepatology 43:316–324.

    Article  PubMed  Google Scholar 

  • Wang X, Willenbring H, Akkari Y, Torimaru Y, Foster M, Al-Dhalimy M, Lagasse E, Finegold M, Olson S, Grompe M. (2003) Cell fusion is the principal source of bone-marrow-derived hepatocytes. Nature 422:897–901.

    Article  PubMed  CAS  Google Scholar 

  • Watanabe M. (2002) Damaged epithelia regenerated by bone marrow-derived cells in the human gastrointestinal tract. Nat Med 8:1011–1017.

    Article  PubMed  Google Scholar 

  • Watanabe T, Nakagawa K, Ohata S, Kitagawa D, Nishitai G, Seo J, Tanemura S, Shimizu N, Kishimoto H, Wada T, Aoki J, Arai H, Iwatsubo T, Mochita M, Watanabe T, Satake M, Ito Y, Matsuyama T, Mak TW, Penninger JM, Nishina H, Katada T. (2002) SEK1/MKK4-Mediated SAPK/JNK Signaling Participates in Embryonic Hepatoblast Proliferation via a Pathway Different from NF-kappaB-Induced Anti-Apoptosis. Dev Biol 250:332–347.

    PubMed  CAS  Google Scholar 

  • Wexler SA, Donaldson C, Denning-Kendall P, Rice C, Bradley B, Hows JM. (2003) Adult bone marrow is a rich source of human mesenchymal “stem” cells but umbilical cord and mobilized adult blood are not. Br J Haematol 121:368–374.

    Article  PubMed  Google Scholar 

  • Willenbring H, Bailey AS, Foster M, Akkari Y, Dorrell C, Olson S, Finegold M, Fleming WH, Grompe M. (2004) Myelomonocytic cells are sufficient for therapeutic cell fusion in liver. Nat Med 10:744–748.

    Article  PubMed  CAS  Google Scholar 

  • Xiao L, Wang K, Teng Y, Zhang J. (2003) Component plane presentation integrated self-organizing map for microarray data analysis. FEBS Lett 538:117–124.

    Article  PubMed  CAS  Google Scholar 

  • Yamamoto N, Terai S, Ohata S, Watanabe T, Omori K, Shinoda K, Miyamoto K, Katada T, Sakaida I, Nishina H, Okita K. (2004) A subpopulation of bone marrow cells depleted by a novel antibody, anti-Liv8, is useful for cell therapy to repair damaged liver. Biochem Biophys Res Commun 313: 1110–1118.

    Article  PubMed  CAS  Google Scholar 

  • Ying QL, Nichols J, Evans EP, Smith AG. (2002) Changing potency by spontaneous fusion. Nature 416:545–548.

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Gastroenterology & Hepatology, Yamaguchi University, Graduate School of Medicine Minami Kogushi 1-1-1, Ube, Yamaguchi, 755-8505, Japan

    Isao Sakaida

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  1. Isao Sakaida
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Editors and Affiliations

  1. Showa University School of Medicine, 1-5-5 Hatanodai, Shinagawa-ku, Tokyo, 142-8555, Japan

    Mitsuo Kusano MD, PhD (Professor of Surgery) & Seiji Shioda MD, PhD (Professor of Anatomy) (Professor of Surgery) &  (Professor of Anatomy)

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© 2007 Springer

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Sakaida, I. (2007). Liver regeneration with the resolution of fibrosis by bone marrow cell infusion therapy. In: Kusano, M., Shioda, S. (eds) New Frontiers in Regenerative Medicine. Springer, Tokyo. https://doi.org/10.1007/978-4-431-38208-9_2

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  • DOI: https://doi.org/10.1007/978-4-431-38208-9_2

  • Publisher Name: Springer, Tokyo

  • Print ISBN: 978-4-431-38207-2

  • Online ISBN: 978-4-431-38208-9

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