General Information

Development

Liver humanized NPG-Fah knockout mice are one of a series of liver injury immunodeficiency mouse models developed independently by Vitonda for transplantation of human primary hepatocytes.

The mouse Fah gene is located on chromosome 7, and CRISPR-Cas9 technology is used to edit exon 1 of the Fah gene to produce indel-induced shifted code mutations, thus realizing the knockout of this gene in NPG mice.The deletion of the Fah gene results in the accumulation of toxic metabolites of tyrosine in the hepatocytes, which leads to extensive and sustained liver damage, and without exogenous drugs or feed control, the hepatocytes will gradually become completely necrotic. Without control by exogenous drugs or feed, the hepatocytes will gradually become completely necrotic, which provides an opportunity for humanized hepatocytes to completely rebuild the mouse liver. Hepatic humanized Fah-deficient mice can be maintained in normal survival by daily administration of NTBC drugs, which is achieved by withdrawal of the drugs when liver injury is required.

Thus, the hepatic humanized NPG-Fah^-/- mouse is an inducible model of liver injury; at the same time, this mouse possesses the NOD background of highly immunized NPG-deficient mice, which supports the co-reconstruction of the humanized liver and hematopoietic/immune system.

Phenotype

1. Peripheral blood human albumin test

Fig1. Peripheral Blood Human Albumin Test of Hu-NPG-Fah KO

Human albumin content in Fah-NPG serum after transplantation of human hepatocytes was assayed by ELISA to detect the reconstitution of human hepatocytes in NPG-Fah knockout mice.The above figure shows the human Alb content at 2 w, 4 w, 6 w, and 7 w postoperatively, and it can be seen that at 6 w post-transplantation, the human albumin content of the humanized NPG-Fah knockout mice could reach more than 4 mg/mL.

Hu-NPG-Fah KO Mice Applications

1. Human-specific liver diseases, drug safety assessment and human-specific liver metabolizing enzymes related research

2. HBV, HCV infection and antiviral activity signaling pathway research

3. Drug metabolism and pharmacokinetics, drug efficacy studies

4. Stem cell research

5. Gene therapy

References

1. Azuma, H. et al. Robust expansion of human hepatocytes in Fah^-/-/Rag2^-/-/Il2rg^-/- mice. Nature biotechnology. 2007, 25, 903-910.

2. Xijun Song, Yushan Guo, Shuguang Duo, et al. A Mouse Model of Inducible Liver Injury Caused by Tet-On Regulated Urokinase for Studies of Hepatocyte Transplantation.The American Journal of Pathology. 2009, 175(5):1975-1983.

3. Foquet L, Wilson EM, Verhoye L, et al. Successful Engraftment of Human Hepatocytes in uPA-SCID and FRG^® KO Mice. Methods Mol Biol. 2017, 1506:117-130.