Biliary Epithelial Cell Physiology and Cholangiopathies
A long-standing focus of the lab is to study the biology of biliary epithelial cells (cholangiocytes) and to understand the pathophysiology of acquired, congenital and neoplastic diseases of the biliary tract (cholangiopathies). Cholangiopathies are rare diseases but are frequent as a group and represent one of the major unmet needs in hepatology.
Emerging evidence furthermore suggests that cholangiocytes participate in the liver repair mechanism of other more common liver diseases.
Acquired cholangiopathies, such as Primary Biliary Cholangitis and Primary Sclerosing Cholangitis are complex multifactorial diseases that are still lacking satisfactory study models. Monogenic cholangiopathies on the other hand, can be considered the “Rosetta Stone” of biliary pathophysiology, as studying their cellular adaptation to the altered function caused by a mutated gene, may reveal a wealth of information about cholangiocyte function.
Cystic fibrosis is a common and severe genetic disease, caused by mutations in CFTR, a membrane protein that mediates the secretion of chloride, bicarbonate and fluids in many secretory epithelia, including the epithelium of the bile ducts. Hepatic complications affect up to 30% of patients with Cystic Fibrosis and affects their survival and quality of life. In these patients, CFTR dysfunction in the biliary epithelium causes progressive chronic cholangitis that develops into biliary cirrhosis.
Alagille syndrome (AGS) is a rare autosomal dominant multisystemic dysmorphogenetic disorder caused by a defective Notch signaling due to mutations in a Notch ligand (JAG1) or, less frequently, in a Notch receptor (NOTCH2). AGS is associated with an incomplete development of the intrahepatic bile ducts; in fact, liver disease is characterized by bile duct paucity, with variable degrees of cholestasis, progressive jaundice, itching, and failure to thrive. Treatment is symptomatic, and liver transplantation is sometimes necessary.
Autosomal Recessive Polycystic Kidney Disease (ARPKD), Congenital Hepatic Fibrosis (CHF) and Caroli’s Disease (CD), are genetic disorders of the kidney and liver caused by defective function of fibrocystin (FPC) or polyductin, the protein encoded by the PKHD1 gene. Despite sharing some common pathological traits, these diseases differ for several aspects, including age of onset.
Polycystic liver diseases, a group of genetic cholangiopathies, are characterized by progressive dilatation of biliary epithelial cysts. The dominant pathology of the adult polycystic kidney (ADPKD) is caused by mutations in the genes that code for ciliary proteins, polycystins. Polycystins function as mechanoreceptors but are also involved in cell differentiation and epithelial morphogenesis. Our recent studies show that angiogenic growth factors, in particular VEGF and Angiopoietin-1, are overexpressed in ADPKD epithelial bile cells (cholangiocytes) and may play a role in the pathogenesis of liver disease. Starting from these observations, the hypothesis of this project is that the autocrine and paracrine angiogenetic signals produced by the biliary epithelium are the key responsible for the growth of liver cysts and the progression of the disease in ADPKD.
PSC is a chronic disease of the biliary tree, characterized by obliterative fibrosis of the intrahepatic and/or extrahepatic bile ducts and chronic portal tract inflammation, eventually leading to cirrhosis and portal hypertension and cholangiocarcinoma. The etiology and pathogenesis of PSC remain unknown. The pathogenesis of PSC is still unknown and the lack of a satisfactory animal or cellular model orthologous to human PSC has hampered the search for a cure.