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

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