Use of optimized pluripotent stem cell derived hepatocytes for evaluation of the biology of viral replication of hepatitis viruses.

Worldwide more than 570 million people are chronically infected by the hepatitis B (HBV) or the hepatitis C virus (HCV) which often leads to cirrhosis and hepatocellular carcinoma. In addition, the hepatitis E virus(HEV) is a potential threat due to the increasing zoonotic transmissionwhich highlights the need for anti-HEV drug development and prevention in the near future. Unfortunately, research of these viruses is hamperedby the lack of cell culture models and by poor virus growth. Currently human hepatoma cell lines are being used to study the biology of virus replication and to develop antiviral agents. However, hepatoma cells mimic only partially normal human hepatocytes and as they originate from cancer tissue their use in hepatitis-mediated oncogenesis studies is questionable. Primary human hepatocytes should facilitate the study of the hepatitis viruses as well as provide a platform for screening new pharmaceuticals. However, shortage of donor organs and culture problems make these cultures expensive and impractical. The proposal aims to demonstrate that human embryonic and induced pluripotent stem cell (hESC/iPSC)-derived hepatocytes are an important novel tool for the evaluation of the biology of hepatotropic viruses. It is our (and others) believe that stem cell-derived hepatocytes will resemble more closely human primary hepatocytes, and may be a renewable source of physiologically more relevant human hepatocytes for studies of hepatitis.