Hepatocyte growth factor gene therapy of liver cirrhosis in rats

Abstract

Liver cirrhosis is the irreversible end result of fibrous scarring and hepatocellular regeneration, characterized by diffuse disorganization of the normal hepatic structure of regenerative nodules and fibrotic tissue1. It is associated with prominent morbidity and mortality, and is induced by many factors, including chronic hepatitis virus infections, alcohol drinking and drug abuse. Hepatocyte growth factor (HGF), originally identified and cloned as a potent mitogen for hepatocytes2,3,4,5, shows mitogenic, motogenic and morphogenic activities for a wide variety of cells6,7,8,9. Moreover, HGF plays an essential part in the development and regeneration of the liver6,7,11, and shows anti–apoptotic activity in hepatocytes11. In a rat model of lethal liver cirrhosis produced by dimethylnitrosamine administrations, repeated transfections of the human HGF gene into skeletal muscles induced a high plasma level of human as well as enodogenous rat HGF, and tyrosine phosphorylation of the c–Met/HGF receptor. Transduction with the HGF gene also suppressed the increase of transforming growth factor–β1 (TGF–β1), which plays an essential part in the progression of liver cirrhosis, inhibited fibrogenesis and hepatocyte apoptosis, and produced the complete resolution of fibrosis in the cirrhotic liver, thereby improving the survival rate of rats with this severe illness. Thus, HGF gene therapy may be potentially useful for the treatment of patients with liver cirrhosis, which is otherwise fatal and untreatable by conventional therapy.

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Figure 1: a, Schedule of DMN administrations and HGF–HVJ liposome or PBS injections.
Figure 2: a–d, Livers were obtained from rats 6 weeks after DMN administration began.
Figure 3: a–c, Liver sections of rats after DMN administration.

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Acknowledgements

We thank F. Anderson and I. Verma for discussions, and K. Nakajo for helping with the analysis of the histopathological study. This work was supported by a Grant–in Aid for Scientific research provided by the Ministry of Education, Science and Culture of Japan (No. 07457282), and by the Public Trust Haraguchi Memorial Cancer Research Fund.

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Correspondence to Jiro Fujimoto.

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Ueki, T., Kaneda, Y., Tsutsui, H. et al. Hepatocyte growth factor gene therapy of liver cirrhosis in rats. Nat Med 5, 226–230 (1999). https://doi.org/10.1038/5593

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