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 non-alcoholic 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. This article is protected by copyright. All rights reserved.

The Spectrum of Reactive Cholangiocytes in Primary Sclerosing Cholangitis

“…The origin of these cholangiocyte‐like cells is still debated and likely depends on the nature of the liver injury. Indeed, in different pathologic settings, they have been shown to originate from reactive cholangiocytes, hepatic and biliary progenitor/stem cells (HPCs), or transdifferentiated hepatocytes/hybrid hepatocytes (sex‐determining region Y‐box 9–positive [Sox9 + ] hepatocyte nuclear factor 4 alpha–positive) . This heterogeneity has rendered the identification of common, specific markers of DRCs quite challenging as different DRCs can express different markers depending on their origin and the nature of the injury .…”

Cholangiocyte‐to‐Hepatocyte Differentiation: A Context‐Dependent Process and an Opportunity for Regenerative Medicine

“…Nevertheless, patients with chronic liver injury exhibit ductular reaction with increased levels of replicating BECs, which correlate with advanced stages of the disease. (1) In this regard, the contribution of the pluripotent BECs, derived from the small ducts of the intrahepatic biliary tree (i.e., canals of Hering), to hepatocyte mass restoration was suggested. Although the first studies reported a modest involvement of BECs in hepatocyte repopulation, (2) recent research work has demonstrated the capacity of BECs to transdifferentiate into hepatocytes upon impaired hepatocyte proliferation.…”

“…Under these circumstances, hepatocytes can enter into replicative senescence, leading to the exhaustion of their proliferative ability, and, therefore, are no longer able to regenerate the hepatic mass. Nevertheless, patients with chronic liver injury exhibit ductular reaction with increased levels of replicating BECs, which correlate with advanced stages of the disease . In this regard, the contribution of the pluripotent BECs, derived from the small ducts of the intrahepatic biliary tree (i.e., canals of Hering), to hepatocyte mass restoration was suggested.…”

Modulation of the Tryptophan Hydroxylase 1/Monoamine Oxidase‐A/5‐Hydroxytryptamine/5‐Hydroxytryptamine Receptor 2A/2B/2C Axis Regulates Biliary Proliferation and Liver Fibrosis During Cholestasis

“…In addition to regulating ductal bicarbonate secretion, cholangiocytes are the target of cholangiopathies, which are liver diseases characterized by ductular reaction, enhanced biliary senescence (with increased secretion of senescence‐associated secretory phenotypes [SASPs]), and subsequent increased collagen deposition . Changes in ductular reaction are modulated by a number of neuroendocrine factors, such as agonists for serotonin receptor subtypes, melatonin, secretin, somatostatin, neurotransmitters, and sex hormones …”