Relevance of the CDE and DDC Mouse Models to Study Ductular Reaction in Chronic Human Liver Diseases

Abstract

The liver has the remarkable capacity to regenerate through cellular division of hepatocytes. However, following severe injuries that abrogates the replicative capacity of hepatocytes some immature-like cells proliferate around the portal area and invade the parenchyma in a process known as ductular reaction (DR). In humans, DR is observed in virtually all chronic liver disorders although the morphological patterns may vary. DR biology has gained considerable interest because of potential contribution to hepatic cell restoration, fibrosis or carcinogenesis. In humans, observational studies are available but experimental manipulations and lineage tracing are impossible. Animal models represent thus valuable tools to explore such questions. Feeding rodents a choline-deficient, ethionine-supplemented diet (CDE) or a diet enriched in 3,5-diethoxycarboncyl-1,4-dihydrocollidine (DDC) are the most popular models to study DR. They are often used equivalently in the literature although the aspects and outcome of the DR are different and model-specific. Here, we describe experimental procedures and the pathophysiological mechanisms at play; we describe the hepatic lesions and highlight the unique character of DR phenotype, proliferation, lineage commitment and microenvironment in each model. We then compare the models with DR phenotype in human pathologies.

Invasive Ductular Reaction Operates Hepatobiliary Junctions upon Hepatocellular Injury in Rodents and Humans

“…10,14 Accordingly, plastination of the bile duct system revealed a denser intrahepatic biliary network in CDE livers. 12 In line with these reports, we show herein that DR expands in the CDE-damaged parenchyma as polarized biliary cells expressing the machinery needed to sense and modify bile. We further show that those biliary ramifications form de novo junctions with the canalicular network, thus establishing a solution of continuity between the primary site of bile secretion Human liver sections from patients with various hepatic disorders were costained for cytokeratin 19 (CK19) and CD10.…”

“…Bile duct obstruction by surgical ligation in BDL or by porphyria plugs in DDC does not cause infiltration of DR into the parenchyma; instead, a denser mesh of interlobular ducts around the portal vein is formed. 12,14,42 In these models, bile retention in bile ducts stimulates the proliferation of cholangiocytes. 43 In BDL, this causes first corrugation of the luminal duct surface, then elongation and branching of interlobular ducts, leading to a fivefold increase of the ductal surface within the portal mesenchyme.…”

“…This is seen in viral hepatitis C or autoimmune disease in humans or in the choline-deficient ethionine-supplemented (CDE) model in rodents. 12 Whether DR is ever responsible for parenchymal reconstitution remains controversial. Parenchymal reconstitution from DR has been suggested in severe acute injury in human livers 15 and in advanced-stage chronic human disease.…”

Role of Oxidative Stress in Hepatic and Extrahepatic Dysfunctions during Nonalcoholic Fatty Liver Disease (NAFLD)

“…Recently, a murine model of nonalcoholic liver disease has been described with liver damage induced through the hepatotoxin administration [ 66 ]. This model produces cholestatic liver failure and develops similar features to patients with NAFLD, including sarcopenia [ 56 ].…”

Liver Regeneration: Different Sub-Populations of Parenchymal Cells at Play Choreographed by an Injury-Specific Microenvironment

“…It is in this setting that the emergence of a ductular reaction (DR) is observed. This term refers to the expansion of small cells with a biliary phenotype either forming pseudo ducts within the portal mesenchyme or invading the lobular parenchyma [64]. DR is not observed following PH.…”