Human Bone Marrow Mesenchymal Stem Cell Transplanted Mouse With Human Liver And Immune System Chimeric Is Adequate To Study HBV Infection Induced Liver Cirrhosis

Hepatitis B virus(HBV)infection and relevant pathophysiological changes lead to liver diseases include severe hepatitis,liver failure,fibrosis,cirrhosis and hepatocellular carcinoma,and cause worldwide burden of public health.Current medications and therapeutic strategies cannot achieve functional cure of HBV infection.Due to its strict species specificity and hepatocyte tropism,humanized animal model is critical for studies of HBV infection mechanism and development of new anti-HBV drugs.However,application of humanized animal model is limited by the drawbacks of primary human hepatocytes include lack of available donor,low expansion in vitro,individual difference and ethical issues.Therefore,establishment of a convenient humanized animal model,especially for the mice with human hepatocytes and immune system dual chimerism is adequate to support further HBV basic research and therapeutic strategies.In this study,we generate a new dual humanized mouse model with syngeneic human hepatocytes and multiple immune cells by transplanting human bone marrow mesenchymal stem cells(hBMSCs)to immunodeficient mouse.Such dual humanized mice are adequate to modeling HBV infection and relevant pathophysiological changes.We reviewed and summarized the aspects of HBV include biological characteristics,epidemiology,natural history of infection,related liver diseases,natural hosts,cells and animal models.Based on the previous research and the investigation of the latest research results,hBMSCs showed great potential for generating a new dual humanized mouse model with syngeneic human hepatocytes and multiple immune cells.We transplant hBMSCs to immunodeficient FRGS mice with fulminant hepatic failure.The syngeneic human hepatocytes and multiple immune cells derived from hBMSCs are demonstrated functional.Cell fusion is not observed between hBMSC-derived human hepatocytes and host mouse hepatocytes.Furthermore,the fulminant hepatic failure microenvironment of the host liver is demonstrated essential for robust transdifferentiation of the implanted hBMSCs.For the first time,we generate a new dual humanized mouse model with syngeneic human hepatocytes and multiple immune cells by transplanting hBMSCs to immunodeficient mouse FRGS mice.Such mice(hBMSC-FRGS)are permissive for chronic infection of the four common HBV genotypes(A,B,C,D)for over 50 weeks.HBV DNA and proteins are detectable in serum and liver of these HBV-infected hBMSC-FRGS mice throughout the infection course.Moreover,infectious HBV particles are observed in serum of such mice.We primarily analysis the relevant pathophysiological changes of the HBV-infected hBMSC-FRGS mice.Intrahepatic human immune cells,cytokines,hepatitis progression and HBV specific antibody levels are detected along with the progression of HBV infection.Our results demonstrated that HBV infection induce sustained hepatitis and immune tolerance in hBMSC-FRGS mice.For the first time,we observed the progression of HBV-induced liver cirrhosis in hBMSC-FRGS mice.After HBV infection,the serological cirrhotic parameters gradually increased,as well as expressions of human liver cirrhosis related genes in hBMSC-FRGS mice liver.Moreover,typical pathological changes of liver cirrhosis are observed.These pathological changes include the accumulation of collagen fibers in the liver tissue,fibrous nodules formation,broken of hepatic lobules structure,collapsed liver plate,rough and solid shrinkage liver surface.Taken together,we hBMSC-FRGS mice with human liver and immune system dual chimerism.Such mice are adequate to support chronic HBV infection,immunopathophysiology and progression of HBV-induced liver cirrhosis.