Myofibroblast Induces Hepatocyte-to-Ductal Metaplasia Via Laminin-ɑvβ6 Integrin in Liver Fibrosis

Background: Liver progenitor cells (LPCs)-mediated liver regeneration sever as the paradigm in liver regeneration. Recent studies demonstrated that hepatocytes undergo the metaplasia into ductal biliary epithelial cells (BECs) in response to chronic injury, and subsequently contribute to liver regeneration. The mechanism underlying hepatocyte-to-ductal metaplasia has not been explored until now. The aim of our study is to investigate the role of myofibroblasts/activated hepatic stellate cells (HSCs) in the conversion of mature hepatocytes into ductal BECs. Methods: The activation of hepatic stellate cells and the expansion of ductal BECs were determined in mouse models of liver fibrosis. Then, we used hepatocyte fate-tracing mouse model to establish the models of liver fibrosis and determined the conversion of mature hepatocytes into ductal BECs. Finally, the mechanism underlying hepatocyte-to-ductal metaplasia was investigated. Findings: A florid ductal BEC response was observed in fibrotic liver, and the depletion of myofibroblasts attenuated ductal BEC expansion remarkably. A hepatocyte fate-tracing model demonstrated the conversion of mature hepatocytes into ductal BECs in fibrotic liver, and the depletion of myofibroblasts diminished the metaplasia. Myofibroblasts secreted laminin-rich ECM, and then laminin induced hepatocyte-to-ductal metaplasia through β6 integrin. Interpretation: Myofibroblasts induce the conversion of mature hepatocytes into ductal BECs through laminin-β6 integrin, which reveals that the strategy improve regeneration in fibrotic liver through the modification of specific microenvironment. Funding: This work was supported by National Natural Science Foundation of China (No.81570555, 81270506). Declaration of Interest: The authors declare that there are no conflicts of interest. Ethical Approval: The protocol of animal treatment used in this study was approved by the institutional animal care and use committee of Tongji Medical College, Huazhong University of Science and Technology.