Panic at the Bile Duct: How Intrahepatic Cholangiocytes Respond to Stress and Injury

Abstract

In the liver, biliary epithelial cells (BECs) line intrahepatic bile ducts (IHBDs) and are primarily responsible for modifying and transporting hepatocyte-produced bile to the digestive tract. BECs comprise only 3% to 5% of the liver by cell number but are critical for maintaining choleresis through homeostasis and disease. To this end, BECs drive an extensive morphologic remodeling of the IHBD network termed ductular reaction (DR) in response to direct injury or injury to the hepatic parenchyma. BECs are also the target of a broad and heterogenous class of diseases termed cholangiopathies, which can present with phenotypes ranging from defective IHBD development in pediatric patients to progressive periductal fibrosis and cancer. DR is observed in many cholangiopathies, highlighting overlapping similarities between cell- and tissue-level responses by BECs across a spectrum of injury and disease. The following core set of cell biological BEC responses to stress and injury may moderate, initiate, or exacerbate liver pathophysiology in a context-dependent manner: cell death, proliferation, transdifferentiation, senescence, and acquisition of neuroendocrine phenotype. By reviewing how IHBDs respond to stress, this review seeks to highlight fundamental processes with potentially adaptive or maladaptive consequences. A deeper understanding of how these common responses contribute to DR and cholangiopathies may identify novel therapeutic targets in liver disease.

Figure 1

Ductular reaction can be classified by parenchymal invasiveness. A: During homeostasis, bile ducts (BD; green) associate closely with the portal vein (PV; blue). B: Noninvasive DR, which is characterized by dilated ducts and minimal expansion of IHBDs away from the portal vein, is typically associated with direct biliary obstruction. C: In contrast, invasive DR is characterized by expansion of the IHBDs into the hepatic parenchyma and often observed with extensive hepatocellular injury. CV, central vein; HA, hepatic artery.

Figure 2

Common cellular responses in DR and cholangiopathies. Biliary epithelial cells mount common cellular responses across a range of liver injuries and diseases. Cell death, proliferation, transdifferentiation, senescence, and acquisition of neuroendocrine phenotype are identified as key features of the biliary epithelial cell stress response.

Figure 3

Biomarkers and pathways associated with biliary epithelial cell responses to stress and injury. Signaling pathways activated in response to direct and indirect stimuli drive functional features of the biliary epithelial cell stress response: transdifferentiation, proliferation, senescence, cell death, and acquisition of neuroendocrine phenotype.