Infection Of Hepatitis B Virus In Extrahepatic Tissues Mediated By Endothelial Progenitor Cells And Bone Marrow Mesenchymal Stem Cells

BackgroundHepatitis B virus (HBV) replication has been reported to be involved inmany extrahepatic viral disorders; however, the mechanism by whichHBV is trans-infected into extrahepatic tissues such as HBV associatedmyocarditis remains largely unknown.ObjectiveIn order to explore whether neogenetic Sprague-Dawley rat cardiacmyocytes, Sprague-Dawley rat bone marrow mesenchymal stemcells(rMSCs), human bone marrow mesenchymal stem cells (hMSCs)and human cord blood endothelial progenitor cells (EPCs) could beinfected by Hepatitis B virus in vitro, and whether hMSCs and EPCshave a function to carry hepatitis B virus to repair damaged tissues invivo.Methods We cultured rat cardiac myocytes, EPCs and MSCs withhepatitis B virus positive serum and then transplantated them intoSprague-Dawley mice of acute myocardial infarction and acute renal ischemic model.ResultsIn this study, we showed that human bone marrow mesenchymal stemcells and human cord blood endothelial progenitor cells, but not ratcardiac myocytes and human umbilical vein endothelial cells could beeffectively infected by uptake of HBV in vitro. Exposure of the cells withHBV resulted in HBV DNA and viral particles were detected in hMSCsand EPCs at day 3 after HBV challenge, which declined thereafter.Consistently, HBV envelope surface and core antigens were first detectedin the cells at day 3 after virus challenge. Significantly, HBV cccDNAwas not detected in EPCs at any time point. In addition, the core antigencan be detected in rat bone marrow mesenchymal stem cells. Furthermore,intravenous transplantation of HBV-treated hMSCs and EPCs intomyocardial infarction and acute renal ischemia mouse model resulted inincorporation of both the stem cells and HBV into heart tissues at theinfarct border zone and other injured extrahepatic tissues such as kidney,lung and liver.ConclusionsNeogenetic Sprague-Dawley rat cardiac myocytes could not be infected,and rat and human bone marrow mesenchymal stem cells could beinfected by hepatitis B virus. It suggests that infection of stem cells byviruses may be one of the mechanisms of emerging zoonotic diseases. These results also strongly support that both EPCs and MSCs serve asvirus carrier mediating HBV trans-infection into the injured tissues. Thefindings might provide a novel mechanism for HBV-associatedmyocarditis and other HBV-related extrahepatic diseases as well. Itsuggests that stem cell have a function to carry viruses to repair sometissues and this may be one of the mechanisms of virus relevant diseaseincluding virus relevant tumor diseases.