Emerging Concepts in Biliary Repair and Fibrosis

Chronic diseases of the biliary tree (cholangiopathies) represent one of the major unmet needs in clinical hepatology and a significant knowledge gap in liver pathophysiology. The common theme in cholangiopathies is that the target of the disease is the biliary tree. After damage to the biliary epithelium, inflammatory changes stimulate a reparative response with proliferation of cholangiocytes and restoration of the biliary architecture, owing to the re-activation of a variety of morphogenetic signals. Chronic damage and inflammation, will ultimately result in pathologic repair, with generation of biliary fibrosis and clinical progression of the disease. The hallmark of pathologic biliary repair is the appearance of reactive ductular cells, a population of cholangiocyte-like epithelial cells of unclear and likely mixed origin, able to orchestrate a complex process that involves a number of different cell types, along with inflammatory and morphogenetic signals. Several questions remain open concerning the histogenesis of reactive ductular cells, their role in liver repair, their mechanism of activation, and the signals exchanged with the other cellular elements cooperating in the reparative process. This review, contributes to the ongoing debate, highlighting a number of new concepts emerging from the study of the pathophysiology of chronic progressive cholangiopathies, such as Congenital Hepatic Fibrosis, Biliary Atresia, and Alagille Syndrome.