Roles Of The Epithelial-Mesenchymal Transition In Histogenesis Of Hepatic Progenitor Cells In HBV-related Liver Diseases

Objective:This study investigated surgical liver specimens from patients with hepatitis B virus-related liver diseases to detect the expression and changes of antigens associated with HPCs and EMT. By this way, we tried to determine whether epithelial-mesenchymal transition(EMT) is involved in the histogenesis of HPCs.Methods:The fresh liver tissue samples of 60 patients with HBV-related liver diseases(including hepatitis and liver cirrhosis) were Collected. For control purposes, 15 biopsy samples were obtained from surgery for other reasons. According to the Metavir scoring system, specimens of hepatitis were scored and further classified as having mild, moderate or severe inflammation on haematoxylin and eosin(H&E) sections. With the cirrhosis group and normal control group, five groups were set up and each sub-group contained fifteen samples. We used double immunofluorescence staining to detect the antigens associated with HPCs(Ep CAM), epithelial cells(CK7 and E-cadherin), EMT(S100A4 and MMP-2) and mesenchymal cells(vimentin and αSMA). Images were acquired and analysed by using a confocal laser scanning microscope, then positive cells count and comparative analysis were carried out.Result:1. Normal parenchymal cells of liver do not express any HPCs(Ep CAM) and EMT(S100A4, MMP- 2 and vimentin) markers except epithelial markers(CK7 and E-cadherin).2. In mild and moderate hepatitis, S100A4-positive cells in DRs expressed HPCs marker Ep CAM. However, some cells only expressed S100A4 but not express Ep CAM.3. In severe hepatitis and cirrhosis, DRs showed expression of MMP-2 and Ep CAM. Some spindle-shaped epithelial cells in DRs expressed vimentin. Some cells which expressed αSMA were present around DRs although DRs were negative for αSMA.4. Started from mild hepatitis, DRs showed increased expression of S100A4 and Ep CAM and with growing inflammation and hepatic fibrosis, the expression of S100A4 was increased. However, their expression decreased significantly in livers of cirrhosis(P<0.05). Similarly, started from severe hepatitis, DRs showed increased expression of MMP-2 and vimentin. Their expression increased significantly in livers of cirrhosis(P<0.05). The reduction expressions of epithelial markers CK7 and E-cadherin paralleled the severity of liver diseases(P<0.05).Conclusion:HPCs, at least in part, may occur from cholangiocytes in DRs and re-transdifferentiate into intermediate hepatocytes through reversing Epithelialmesenchymal transition(EMT) in HBV-related liver diseases.