The instructive scar - the dynamic role of extracellular matrix in biliary pathophysiology

Cholangiopathies - congenital and acquired diseases of the hepatic bile ducts within the liver - are often considered rare pathologies but contribute to a significant proportion of all liver transplantations. Cholangiopathies present a challenge in the clinic, often due to a lack of targeted, specific therapies, thereby underscoring the need for the development of new treatments. As with many chronic diseases, cholangiopathies exist as a spectrum; they are associated with increased inflammation and fibrosis throughout disease progression that, ultimately, result in reduced liver function and increased likelihood of developing biliary tract cancers (cholangiocarcinoma). Fibrotic scarring surrounding diseased bile ducts is characterised by aberrant changes to the molecular composition of the extracellular matrix. The contribution of individual cell types to the deposition and remodelling of the extracellular matrix, as well as its molecular composition, varies between cholangiopathies. Although a broad-strokes characterisation of the extracellular matrix is well established, how it conveys biochemical and biomechanical signals to the biliary epithelial cells (cholangiocytes) and how these interactions inform ductular cells to coordinate tissue-level regeneration and underpin the molecular pathology of the cholangiopathies is not well understood. In this Review, we explore the mechanisms and roles of an altered extracellular matrix in cholangiopathies and discuss the current and future perspectives for therapeutic strategies for targeting these processes in the clinic to intervene in cholangiopathies.