Development of an HSV-tk transgenic mouse model for study of liver damage.

The herpes simplex virus thymidine kinase/ganciclovir (HSV-tk/GCV) system that selectively depletes cells expressing HSV-tk upon treatment with GCV has provided a valuable tool for developing a new animal model expressing the desired tissue damage. In this paper, an HSV-tk vector with an albumin promoter/enhancer was constructed. Based on the favourable killing effect on Hep-G2 cells by the recombinant construct, the HSV-tk transgenic mouse strains were developed. One strain of the TK transgenic mouse (TK5) was studied intensively. Integration of the target gene was confirmed primarily by PCR. Fluorescence in situ hybridization following G-banding analysis demonstrated that the insertion site was located at 2F1-G3. The hepatocyte-specific transcription and expression of HSV-tkwas verified by reverse transcription (RT)-PCR as well as by immunohistochemical staining. When two second-generation mice (TK5-F1 and TK5-F2) were injected with GCV, the pathogenic alterations in the liver were readily identified, including the appearance of vaculation in the hepatocytes with inflammatory infiltration in the liver, and diffuse proliferation of hepatocytes. In addition, the blood test demonstrates a significant increase of serum alanine aminotransferase, aspartate aminotransferase and total bilirubin. In conclusion, the transgenic mouse model with hepatocyte-specific expressed HSV-tk developed hepatitis with administration of GCV, had morphological and clinical chemical characteristics indicative of hepatocellular disease and should be useful for the the study of inducible liver-specific diseases.