Salk Institute for Biological Studies: InsideSalk

Chimeric Mouse Developed to Test Human Liver Disease

Mouse Liver Cells

Mouse liver containing 95 percent human hepatocytes.

A team led by Salk Institute researchers has developed a mouse model with 95 percent of its liver containing cells of human origin, making it an ideal system to test novel therapies for debilitating human diseases, including cancer.

The team, led by senior author Inder Verma, a professor in the Laboratory of Genetics, had previously generated a mouse with a partially "humanized" liver, but wanted to improve their method to achieve almost complete transformation. They use a special mouse that has liver problems of its own, but whose problems can be kept in check with a drug called NBTC. Taking away NBTC allows human hepatocytes to take hold and populate the mouse liver with human cells.

The new model is susceptible to human liver infections and responds to human drug treatments. To test this, the researchers exposed the mice to Hepatitis B and Hepatitis C and found that, unlike normal mice, that are resistant to these viruses, the chimeric animals developed the disease.

More importantly, using pegylated interferon alpha 2a – the standard treatment for Hepatitis C – the researchers showed that the "humanized" liver inside the mouse responds just like a normal human liver. The team tested additional experimental drugs and found that they too behaved as they did in humans.

"This shows that our chimeric mouse model is medically relevant and can be used to validate novel drugs in a pre-clinical setting," says first author Karl-Dimiter Bissig, an internist and postdoctoral researcher in the Laboratory of Genetics. "This is great news as it provides us with a tool with which we can examine many human hepatotropic pathogens, including malaria. In the future, it also has potential applications for regenerative medicine; allowing confirmation of the true hepatocyte nature of cells prior to human transplantation."

The study was published in the online edition of the Journal of Clinical Investigation in February.

InsideSalk 04|10 Issue | © Salk Institute for Biological Studies