Hepatocyte growth factor in liver sinusoidal endothelial cells regulates hepatitis B virus replication in hepatocytes

The relationship between hepatitis B virus (HBV)-infected hepatocytes and hepatic non-parenchymal cells is crucial for sustaining the pathological conditions of hepatitis B. However, the effects of endothelial cells on viral replication in HBV-infected hepatocytes remain unclear. To investigate this role, we designed direct and indirect co-culture systems comprising HBV-infected hepatocytes and endothelial cells. Our findings showed that endothelial cells potentiated viral replication in HBV-infected hepatocytes. However, antibodies against hepatocyte growth factor (HGF), a humoral factor secreted by endothelial cells, attenuated the upregulated viral replication observed in HBV-infected hepatocytes co-cultured with endothelial cells. In addition, HGF dose-dependently upregulated viral replication in HBV-infected hepatocytes, reaching a peak at 5–10 ng/ml. In terms of the intracellular signaling pathways downstream of the c-Met receptor, to which HGF binds, the STAT3 and PI3K–Akt–mTOR pathways were correlated with viral replication in HBV-infected hepatocytes co-cultured with endothelial cells or treated with HGF. Furthermore, both endocytosis and lysosome inhibitors individually blocked the HGF dose-dependent increase in viral replication in HBV-infected hepatocytes. In conclusion, our study provides novel evidence that endothelial cells secrete HGF to dose-dependently modulate viral replication in HBV-infected hepatocytes within the microenvironment of hepatitis B.