Abstract
Rodents are commonly employed to model human liver conditions, although species differences can restrict their translational relevance. To overcome some of these limitations, researchers have long pursued human hepatocyte transplantation into rodents. More than 20 years ago, the first primary human hepatocyte transplantations into immunodeficient mice with liver injury were able to support hepatitis B and C virus infections, as these viruses cannot replicate in murine hepatocytes. Since then, hepatocyte chimeric mouse models have transitioned into mainstream preclinical research and are now employed in a diverse array of liver conditions beyond viral hepatitis, including malaria, drug metabolism, liver-targeting gene therapy, metabolic dysfunction-associated steatotic liver disease, lipoprotein and bile acid biology, and others. Concurrently, endeavors to cotransplant other cell types and humanize immune and other nonparenchymal compartments have seen growing success. Looking ahead, several challenges remain. These include enhancing immune functionality in mice doubly humanized with hepatocytes and immune systems, efficiently creating mice with genetically altered grafts and reliably humanizing chimeric mice with renewable cell sources such as patient-specific induced pluripotent stem cells. In conclusion, hepatocyte chimeric mice have evolved into vital preclinical models that address many limitations of traditional rodent models. Continued improvements may further expand their applications.