Relevance of the CDE and DDC mouse models to study ductular reaction in chronic human liver diseases

Clerbaux, Laure-Alix [UCL] Van Hul, Noemi Gouw, ASH Manco, Rita [UCL] Espanol-Sune, Regina Leclercq, Isabelle [UCL]

The liver has the remarkable capacity to regenerate through cellular division of hepatocytes. However, following severe or chronic 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 their potential contribution to hepatic cell restoration, fibrosis or carcinogenesis. In humans, observational studies are available but experimental manipulations and of lineage tracing are impossible. Animal models represent thus valuable tools to explore such questions. The two most popular models of chronic liver damage inducing DR are dietary models: a choline-deficient, ethionine-supplemented diet (CDE) and a diet enriched in 3,5-diethoxycarboncyl-1,4-dihydrocollidine (DDC). They are often used equivalently in the literature although the aspects and outcome of the DR are different and model-specific. Here, we describe the pathophysiological mechanisms at play in each model and the experimental procedures to induce DR with the CDE and DDC diet. We then describe the hepatic lesions and highlight the unique character of each model with regards to the DR phenotype, proliferation, lineage commitment and microenvironment. When compared to chronic human liver diseases, the DR phenotype and signaling pathways in the CDE model mirror those of DR in chronic hepatitis C infection and in autoimmune hepatitis, while the DDC model mimics DR of chronic biliary injury. A better characterization of DR mouse models will help our understanding of the diversity of DR patterns observed in humans and will help the researchers to select the appropriate model in relation to the scientific question.