Generation of a humanized mouse model with both human immune system and liver cells to model hepatitis C virus infection and liver immunopathogenesis

Abstract

Establishing a small animal model that accurately recapitulates hepatotropic pathogens, including hepatitis C virus (HCV) infection and immunopathogenesis, is essential for the study of hepatitis virus–induced liver disease and for therapeutics development. This protocol describes our recently developed humanized mouse model for studying HCV and other hepatotropic infections, human immune response and hepatitis and liver fibrosis. The first 5-h stage is the isolation of human liver progenitor and hematopoietic stem cells from fetal liver. Next, AFC8 immunodeficient mice are transplanted with the isolated progenitor/stem cells. This generally takes 2 h. The transplanted mice are then treated for a month with the mouse liver apoptosis–inducing AFC8 dimerizer and left for an additional 2-month period to permit human liver and immune cell growth as well as system reconstitution and development before inoculation with HCV clinical isolates. HCV infection, human immune response and liver disease are observed with high incidence from approximately 2 months after inoculation.

Metalloproteinases in liver fibrosis: current insights

“…Finally, humanized mice with human immune system and hepatocytes is the only model, which upon infection triggers responses similar to humans, i.e., hepatitis and fibrosis. [44][45][46][47] Genetically modified mice Genetically modified animals are becoming a more frequent tool to study liver pathophysiology as well as the roles of metalloproteinases. The liver consists of several cell types and it is not easy to target them specifically.…”

SCID pigs: An emerging large animal NK model

“…Although attempts at humanization of available pig has not yet been published, mature teratomas developed after injection of human pluripotent stem cell injection into RAG mutant SCID pigs 35 . The success of the SCID mouse for xenotransplantation, cancer therapy, human specific disease modeling, and stem cell therapies is well documented 43,44,46 and can be expected to extend to swine models. Swine immune parameters more similar to the human, as described above, and in addition, the swine immune gene component or "immunome" is very similar to humans 47 …”

“…Coveted for the lack of xenograft rejection and human tissue differentiation, humanized mice can provide the environment to harbor and allow differentiation of human HSC 43 , allowing a model of human immune response to host species-restricted pathogens such as HIV or hepatitis C virus 44 . Early research on various strains of humanization of SCID mouse variants identified that potential mouse cell to human cell interactions were interfering with engraftment success.…”

The search for precision models clinically relevant to human liver cancer

“…Similarly, hepatitis B virus X transgenic mice develop liver tumors after 13-24 months [19]. A humanized mouse model to model HCV infection has also been established [20]. Abusive alcohol consumption is another leading cause of liver damage and a contributive factor for cirrhosis and liver cancer [21].…”