The liver is known as a robust organ. Its regenerative capacity has been recognized already in ancient Greek mythology in the story of Prometheus. Unlike other regenerative tissues that contain dedicated stem cells (e.g. skin, intestine), the liver can regenerate cells from mature differentiated cells, which upon stimuli reprogram their fate and even switch into another cell type. However, some disease conditions hamper this remarkable cell plasticity and the liver’s capacity to recover. Deeper fundamental understanding of endogenous regenerative processes is therefore crucial for the development of any promising therapeutic strategy to avoid the most drastic solution, which is a liver transplant.
This project studied mechanisms of cell plasticity in the liver, in the context of cholestatic liver diseases, exemplified by the rare disease Alagille syndrome. Because of gene mutations affecting the Notch signalling pathway, Alagille syndrome presents with a range of phenotypes in many organs, including a severe underdevelopment of intrahepatic bile ducts at birth, resulting in cholestasis, jaundice, pruritus (skin itching), and other complications. The severity of the Alagille syndrome liver phenotype varies broadly and, astonishingly, some individuals recover bile ducts with full function later in life.
Bile ducts are a tree-like structure in the liver, branching from the centre of the organ. They collect bile from the organ periphery and carry it out of the liver, relying on a proper arrangement of cells in the bile duct epithelium. Previous studies in a mouse model of the disease showed that bile duct regeneration is spatially heterogeneous, with the bile ducts recovering differently in the centre and at the periphery of the organ, suggesting distinct mechanisms at play.
This project aimed to determine mechanisms that contribute to the recovery of bile ducts and underlie the regional heterogeneity of this process by using state-of-the-art gene expression profiling methods and advanced microscopy approaches in mouse models. With these data, we aimed to identify molecular pathways for potential intervention in the treatment of cholestatic liver.
