Ductular Reaction in Liver Diseases: Pathological Mechanisms and Translational Significances

Abstract

Ductular reaction (DR) is characterized by the proliferation of reactive bile ducts induced by liver injuries. DR is pathologically recognized as bile duct hyperplasia and is commonly observed in biliary disorders. It can also be identified in various liver disorders including nonalcoholic fatty liver disease. DR is associated with liver fibrosis and damage, and the extent of DR parallels to patient mortality. DR raises scientific interests because it is associated with transdifferentiation of liver cells and may play an important role in hepatic regeneration. The origin of active cells during DR can be cholangiocytes, hepatocytes, or hepatic progenitor cells, and associated signaling pathways could differ depending on the specific liver injury or animal models used in the study. Although further studies are needed to elucidate detailed mechanisms and the functional roles in liver diseases, DR can be a therapeutic target to inhibit liver fibrosis and to promote liver regeneration. This review summarizes previous studies of DR identified in patients and animal models as well as currently understood mechanisms of DR.

Figure 1. Location of cholangiocytes, HPCs, and hepatocytes in the liver

Identified markers for these cells are shown in green, red, and orange, respectively.

Figure 2. Types of DR

During cholangiocyte damage, cholangiocytes and/or HPCs proliferate to compensate biliary cell population and functions. Hepatocytes transdifferentiate into cholangiocytes and/or biliary-like cells that have different gene expression profiles. During hepatocyte damage, cholangiocytes start proliferation and transdifferentiate into hepatocytes via HPCs. The types of DR and the origin of active cells vary depending on liver injuries or experimental conditions.

Figure 3

Pathways of DR-associated transdifferentiation. Hippo/YAP/Notch signaling as well as HGF/c-Met signaling are associated with transdifferentiation into cholangiocytes, and Wnt/β-catenin signaling is associated with transdifferentiation into hepatocytes. Expression levels of stem cell or oval cell markers such as A6 and OV6 are elevated during this process. Although TWEAK/Fn14 signaling induces HPC and/or cholangiocyte proliferation, it is unclear whether this signaling is required for transdifferentiation of liver cells. It is also unclear whether hepatocytes and/or cholangiocytes transdifferentiate directly or via HPCs. Previous studies indicate senescent hepatocytes may trigger transdifferentiation leading to DR and liver regeneration.