![]() ![]() ![]() It is uncertain whether HCT is beneficial or detrimental to the liver. In addition, there are few studies regarding the actual effects of HCT on liver structural regeneration and functional repair in chronic liver injury. ![]() However, the origin of cholangiocytes in DR due to chronic hepatocytic injuries, such as hepatitis B virus (HBV) infection, nonalcoholic steatohepatitis (NASH), and alcoholic liver disease (ALD), remains unclear. In the study of cholestatic liver diseases, hepatocyte-cholangiocyte transdifferentiation (HCT), a process in which hepatocytes transdifferentiate into cholangiocytes, was described. Unlike hepatocyte mitosis, the cholangiocytes in DR may originate from putative hepatic progenitor cells (HPCs), which are difficult to determine in human tissue studies. Proliferation of cholangiocytes, also known as ductular reaction (DR), is commonly presented in liver regeneration from chronic injury. The transdifferentiation between hepatocytes and cholangiocytes has been observed. However, when insulted by prolonged chronic injury, the exhausted regeneration potential of liver parenchymal cells is usually insufficient to complete tissue repair only by their own mitosis and proliferation. The unique regenerative capacity of the liver in acute injury is always beneficial and has been extensively studied. Under normal conditions, hepatocytes and cholangiocytes maintain a low turnover rate to compensate for occasional cell loss, such as apoptosis and senescence. The liver parenchyma, comprised of hepatocytes and cholangiocytes, accounts for 70–80% of the total liver mass and maintains hepatic homeostasis. Inhibition of COX-2 could ameliorate HCT through the COX-2-TGF-β-TGFBR1-β-catenin pathway and improve liver function. ConclusionsĪtypical cholangiocytes can be derived from HCT, which forms a secondary strike by maldevelopment of the bile drainage system and BA homeostasis disequilibrium during chronic liver injury. The COX-2 selective inhibitor etoricoxib suppressed HCT through the TGF-β-TGFBR1-β-catenin pathway in vitro. Genetic deletion or pharmaceutical inhibition of COX-2 significantly reduced HCT in vivo. The structure of the biliary system was impaired, and BA metabolism was dysregulated by HCT, which was mediated by the TGF-β/β-catenin signaling pathway. Immunofluorescence and RNA sequencing indicated that atypical cholangiocytes were characterized by an intermediate genetic phenotype between hepatocytes and cholangiocytes and might be derived from hepatocytes. ![]() Intrahepatic ductular reaction was associated with COX-2 upregulation in chronic liver injury. Either a COX-2 selective inhibitor or a β-catenin pathway inhibitor was administered in vitro. Serum and liver bile acid (BA) concentrations were measured. The biliary tract was injected with ink and visualized by whole liver optical clearing. HCT was identified by costaining of hepatocyte and cholangiocyte markers in vivo and in isolated mouse hepatocytes in vitro. MethodsĪ thioacetamide (TAA)-induced liver injury model was established in wild-type (WT-TAA group) and COX-2 panknockout (KO-TAA group) mice. This study aimed to determine HCT after chronic liver injury, verify the impacts of HCT on liver repair, and avoid harmful regeneration by understanding the mechanism. Hepatocyte-cholangiocyte transdifferentiation (HCT) is a potential origin of proliferating cholangiocytes in liver regeneration after chronic injury. ![]()
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