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Adeno-associated virus vector-mediated production of hepatocyte growth factor attenuates liver fibrosis in mice

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Abstract

Purpose

Adeno-associated virus (AAV) vectors can achieve long-term gene expression and are now feasible for use in human gene therapy. We constructed hepatocyte growth factor (HGF) expressing AAV (AAV5-HGF) and examined its effect in two mouse hepatic fibrosis models.

Methods

A model of hepatic fibrosis was established by carbon tetrachloride (CCl4) administration in Balb/c mice. After the establishment of liver fibrosis, AAV5-HGF was injected once into the portal vein. Mice were killed 3, 6, 9, and 12 weeks after injection. Another model was established by bile duct ligation (BDL). Seven weeks after AAV5-HGF injection, mice underwent BDL, and were then killed 2 weeks after BDL.

Results

Mice that received AAV5-HGF achieved stable HGF expression both in the serum and liver for at least 12 weeks. In both models, significant improvement of the liver fibrosis was found in all mice receiving AAV5-HGF based on Azan-Mallory staining. Suppression of hepatic stellate cells (HSC) was confirmed by immunohistochemistry. Fibrogenic markers were significantly suppressed and collagenase activity increased in the livers of mice receiving AAV5-HGF.

Conclusions

A single injection of AAV vector containing HGF gene achieved long-term expression of HGF and resulted in resolution of mouse liver fibrosis. HGF gene therapy mediated by AAV is feasible for the treatment of liver fibrosis.

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Abbreviations

AAV:

Adeno-associated virus

BDL:

Bile duct ligation

CCl4 :

Carbon tetrachloride

HGF:

Hepatocyte growth factor

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Acknowledgements

This work was supported by Grant-in-aid for Scientific Research (No. 11470266) from Japan Society for the Promotion of Science and the Ministry of Health.

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Authors and Affiliations

  1. First Department of Surgery, Hyogo College of Medicine, 1-1 Mukogawacho, Nishinomiya, Hyogo, 663-8501, Japan

    Kazuhiro Suzumura, Tadamichi Hirano, Gakuhei Son, Yuji Iimuro & Jiro Fujimoto

  2. Division of Genetic Therapeutics, Center for Molecular Medicine, Jichi Medical University, Shimotsuke, Tochigi, 329-0498, Japan

    Hiroaki Mizukami & Keiya Ozawa

Authors
  1. Kazuhiro Suzumura
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  2. Tadamichi Hirano
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  3. Gakuhei Son
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  7. Jiro Fujimoto
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Correspondence to Jiro Fujimoto.

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Suzumura, K., Hirano, T., Son, G. et al. Adeno-associated virus vector-mediated production of hepatocyte growth factor attenuates liver fibrosis in mice. Hepatol Int 2, 80–88 (2008). https://doi.org/10.1007/s12072-007-9042-1

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  • DOI: https://doi.org/10.1007/s12072-007-9042-1

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