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Administration of fibroblast growth factor 2 in combination with bone marrow transplantation synergistically improves carbon-tetrachloride-induced liver fibrosis in mice

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Abstract

We previously reported that fibroblast growth factor 2 (FGF2) facilitated the differentiation of transplanted bone marrow cells (BMCs) into hepatocytes. Our earlier study also demonstrated that administration of FGF2 in combination with bone marrow transplantation (BMT) synergistically activated tumor necrosis factor-alpha signaling and significantly improved liver function and prognosis more than BMT alone. However, the way that it affected the extracellular matrix remained unclear. Here, we investigated the effect of FGF2 treatment together with BMT on liver fibrosis in mice treated with carbon tetrachloride (CCl4). Transplantation of BMCs and concurrent treatment with FGF2 caused a statistically significant reduction in CCl4-induced liver fibrosis that was accompanied by strong expression of matrix metalloproteinase 9 as compared with FGF2-only treatment or BMT alone. Moreover, in this process, the proliferation of bone-marrow-derived cells was accelerated without causing apoptosis. Thus, the administration of FGF2 in combination with BMT synergistically improves CCl4-induced liver fibrosis in mice. This treatment has the potential of being an effective therapy for patients with liver cirrhosis.

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Abbreviations

BMC:

bone marrow cell

GFP:

green fluorescent protein

CCl4 :

carbon tetrachloride

BMT:

bone marrow transplantation

FGF2:

fibroblast growth factor 2

TNFα:

tumor necrosis factor α

ECM:

extracellular matrix

MMP:

matrix metalloproteinase

NFκB:

nuclear factor κ B

TIMP:

tissue inhibitor of metalloproteinase

rFGF:

recombinant fibroblast growth factor

αSMA:

alpha-smooth muscle actin

TUNEL:

terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labeling

TdT:

terminal deoxynucleotidyl transferase

dUDT:

deoxyuridine triphosphate

References

  • Bezerra JA, Bugge TH, Melin-Aldana H, Sabla G, Kombrinck KW, Witte DP, Degen JL (1999) Plasminogen deficiency leads to impaired remodeling after a toxic injury to the liver. Proc Natl Acad Sci USA 96:15143–15148

    Article  PubMed  CAS  Google Scholar 

  • Emonard H, Hornebeck W (2000) Matrix metalloproteinases (MMPs). In: Bikfalvi A (ed) Encyclopedic reference of vascular biology and pathology. Springer, Berlin Heidelberg New York, pp 172–181

    Google Scholar 

  • Ferrari G, Cusella-De Angelis G, Coletta M, Paolucci E, Stornaiuolo A, Cossu G, Mavilio F (1998) Muscle regeneration by bone marrow-derived myogenic progenitors. Science 279:1528–1530

    Article  PubMed  CAS  Google Scholar 

  • Fleming TJ, Fleming ML, Malek TR (1993) Selective expression of Ly-6G on myeloid lineage cells in mouse bone marrow. RB6-8C5 mAb to granulocyte-differentiation antigen (Gr-1) detects members of the Ly-6 family. J Immunol 151:2399–2408

    PubMed  CAS  Google Scholar 

  • Hozumi A, Nishimura Y, Nishiuma T, Kotani Y, Yokoyama M (2001) Induction of MMP-9 in normal human bronchial epithelial cells by TNF-alpha via NF-kappa B-mediated pathway. Am J Physiol Lung Cell Mol Physiol 281:L1444–L1452

    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 (2006) Fibroblast growth factor 2 facilitates the differentiation of transplanted bone marrow cells into hepatocytes. Cell Tissue Res 323:221–231

    Article  PubMed  CAS  Google Scholar 

  • Kim TH, Mars WM, Stolz DB, Petersen BE, Michalopoulos GK (1997) Extracellular matrix remodeling at the early stages of liver regeneration in the rat. Hepatology 26:896–904

    Article  PubMed  CAS  Google Scholar 

  • Kotton DN, Ma BY, Cardoso WV, Sanderson EA, Summer RS, Williams MC, Fine A (2001) Bone marrow-derived cells as progenitors of lung alveolar epithelium. Development 128:5181–5188

    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 

  • 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 

  • Li YL, Sato M, Kojima N, Miura M, Senoo H (1999) Regulatory role of extracellular matrix components in expression of matrix metalloproteinases in cultured hepatic stellate cells. Cell Struct Funct 24:255–61

    Article  PubMed  CAS  Google Scholar 

  • Liu JF, Crepin M, Liu JM, Barritault D, Ledoux D (2002) FGF-2 and TPA induce matrix metalloproteinase-9 secretion in MCF-7 cells through PKC activation of the Ras/ERK pathway. Biochem Biophys Res Commun 293:1174–1182

    Article  PubMed  CAS  Google Scholar 

  • Mars WM, Kim TH, Stolz DB, Liu ML, Michalopoulos GK (1996) Presence of urokinase in serum-free primary rat hepatocyte cultures and its role in activating hepatocyte growth factor. Cancer Res 56:2837–2843

    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 

  • Orlic D, Kajstura J, Chimenti S, Jakoniuk I, Anderson SM, Li B, Pickel J, McKay R, Nadal-Ginard B, Bodine DM, Leri A, Anversa P (2001) Bone marrow cells regenerate infarcted myocardium. Nature 410:701–705

    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 

  • Sakaida I, Nagatomi A, Hironaka K, Uchida K, Okita K (1999) Quantitative analysis of liver fibrosis and stellate cell changes in patients with chronic hepatitis C after interferon therapy. Am J Gastroenterol 94:489–496

    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 

  • Serandour AL, Loyer P, Garnier D, Courselaud B, Theret N, Glaise D, Guguen-Guillouzo C, Corlu A (2005) TNFalpha-mediated extracellular matrix remodeling is required for multiple division cycles in rat hepatocytes. Hepatology 41:478–486

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Springer T, Galfre G, Secher DS, Milstein C (1979) Mac-1: a macrophage differentiation antigen identified by monoclonal antibody. Eur J Immunol 9:301–306

    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 (Tokyo) 134:551–558

    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 

Download references

Acknowledgements

We thank Dr. Masaru Okabe (Osaka University) for the gift of GFP transgenic mice and Mr. Jun Oba for valuable technical support.

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Authors and Affiliations

  1. Department of Molecular Science and Applied Medicine (Gastroenterology and Hepatology), Yamaguchi University School of Medicine, Minami Kogushi 1-1-1, Ube, Yamaguchi, 755-8505, Japan

    Tsuyoshi Ishikawa, Shuji Terai, Yohei Urata, Yoshio Marumoto, Koji Aoyama, Yuko Mizunaga, Naoki Yamamoto & Isao Sakaida

  2. Science Research Center, Yamaguchi University, Minami Kogushi 1-1-1, Ube, Yamaguchi, 755-8505, Japan

    Tomoaki Murata

  3. Department of Developmental and Regenerative Biology, Medical Research Institute, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8510, Japan

    Hiroshi Nishina

  4. Department of Neuroanatomy and Neuroscience, Yamaguchi University School of Medicine, Minami Kogushi 1-1-1, Ube, Yamaguchi, 755-8505, Japan

    Koh Shinoda

Authors
  1. Tsuyoshi Ishikawa
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  2. Shuji Terai
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  3. Yohei Urata
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  4. Yoshio Marumoto
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  5. Koji Aoyama
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  6. Tomoaki Murata
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  7. Yuko Mizunaga
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  8. Naoki Yamamoto
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  9. Hiroshi Nishina
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  10. Koh Shinoda
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  11. Isao Sakaida
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Corresponding author

Correspondence to Shuji Terai.

Additional information

This study was supported by Grants-in-Aid for Scientific Research from the Japan Society for the Promotion of Science (nos. 16390211 and 16590597) and for translational research from the Ministry of Health, Labor and Welfare (H-trans-5 and H17-Special-015).

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Ishikawa, T., Terai, S., Urata, Y. et al. Administration of fibroblast growth factor 2 in combination with bone marrow transplantation synergistically improves carbon-tetrachloride-induced liver fibrosis in mice. Cell Tissue Res 327, 463–470 (2007). https://doi.org/10.1007/s00441-006-0334-x

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  • DOI: https://doi.org/10.1007/s00441-006-0334-x

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