Efficient liver repopulation of transplanted hepatocyte prevents cirrhosis in a rat model of hereditary tyrosinemia type i

Hereditary tyrosinemia type I (HT1) is caused by a deficiency in the enzyme fumarylacetoacetate hydrolase (Fah). Fah-deficient mice and pigs are phenotypically analogous to human HT1, but do not recapitulate all the chronic features of the human disorder, especially liver fibrosis and cirrhosis. Rats as an important model organism for biomedical research have many advantages over other animal models. Genome engineering in rats is limited till the availability of new gene editing technologies. Using the recently developed CRISPR/Cas9 technique, we generated Fah ^-/- rats. The Fah ^-/- rats faithfully represented major phenotypic and biochemical manifestations of human HT1, including hypertyrosinemia, liver failure, and renal tubular damage. More importantly, the Fah ^-/- rats developed remarkable liver fibrosis and cirrhosis, which have not been observed in Fah mutant mice or pigs. Transplantation of wild-type hepatocytes rescued the Fah ^-/- rats from impending death. Moreover, the highly efficient repopulation of hepatocytes in Fah ^-/- livers prevented the progression of liver fibrosis to cirrhosis and in turn restored liver architecture. These results indicate that Fah ^-/- rats may be used as an animal model of HT1 with liver cirrhosis. Furthermore, Fah ^-/- rats may be used as a tool in studying hepatocyte transplantation and a bioreactor for the expansion of hepatocytes.