Human Liver Cell Expansion in a Porcine Model

Statistics from the American Liver Foundation show that hepatitis, cirrhosis and hepatocellular carcinoma (HCC) affect 25 million Americans. Unfortunately, liver disease research lags behind other well-studied, prominent disorders because appropriate animal models do not exist.

To address the need for a large animal model of HCC arising spontaneously within a background of regenerative nodules and cirrhosis, Dr. Nyberg and colleagues have recently developed the first porcine model of hereditary tyrosinemia type 1 (HT1)1.

In humans, HT1 results in hepatic failure, cirrhosis and HCC early in childhood and is caused by deficiency in the enzyme fumarylacetoacetate hydrolase (FAH).

The Fah-null porcine model — created by targeting and disrupting the porcine Fah gene — was phenotypically normal, but had decreased Fah transcriptional and enzymatic activity as compared to wild-type animals. Dr. Nyberg and colleagues anticipate using the new model for gene and cell therapy research, particularly for studies related to hepatocyte and bone marrow transplantation.

Alternatively, the group sees the HT1 pigs as an in vivo incubator to grow hepatocytes — liver cells — from humans, something previously done using Fah mutant mice.2 The hepatocytes generated in the mice were fully functioning adult primary hepatocytes able to perform all the necessary functions required in a normal human liver.

Since the absolute number of primary human hepatocytes obtainable from the mice is low, replicating this success in the larger porcine model is highly desirable, as large numbers of human cells are needed for extracorporeal liver assist devices such as the bioartificial liver.

The HT1 pig may also be used to grow patient-specific hepatocytes for cell transplantation, avoiding the need for immunosuppression after transplantation.

References
  1. Hickey RD, et al. Efficient production of Fah-null heterozygote pigs by chimeric adeno-associated virus-mediated gene knockout and somatic cell nuclear transfer. Hepatology. 2011.
  2. Azuma H, et al. Robust expansion of human hepatocytes in Fah-/-/Rag2-/-/Il2rg-/- mice. Nature Biotechnology. 2007;25:903.