Morphological and functional heterogeneity of the mouse intrahepatic biliary epithelium

In recent years, knowledge associated with biliary epithelial cell (i.e., cholangiocytes) function has been significantly enhanced due to increased interest in cholestatic liver diseases, biliary fibrosis, and biliary cancer (1-6). Cholangiocytes were originally termed as ‘simple’ epithelia, which line the intrahepatic and extrahepatic bile ducts (7-9). Despite the original terminology of ‘simple epithelia’, cholangiocytes play an important role in the modification of ductal bile, as well as in the detoxification of xenobiotics (1, 2, 10, 11). In diseases of the biliary tree (i.e., cholangiopathies) such as primary sclerosing cholangitis (PSC), primary biliary cirrhosis (PBC), liver allograft rejection and graft-versus-host disease), cholangiocytes are the target cells (1, 3). Cholangiopathies cause morbidity and mortality and are a major reason for liver transplantation (1, 3) and graft loss (12). Cholangiopathies are characterized by patchy rather than diffuse proliferation and loss of different sized ducts, which suggest that cholangiocytes are heterogeneous and respond differentially to cholestatic diseases and toxin-induced liver injury (1, 5, 13). Recently, the concept of heterogeneity of the rat biliary epithelium has been explored (1, 5, 7, 8, 10, 13-18) and classified into three categories: (i) morphological (7, 8, 14); (ii) secretory (7, 14, 16); and (iii) proliferative (5, 10, 13, 15, 17-19). Morphological heterogeneity— In humans, the biliary ductal system is classified into three different sized segments, which include the extrahepatic bile duct, large bile ducts and intrahepatic small bile ducts (1, 6, 9). The biliary system extends from the canals of Hering to the large extrahepatic ducts (1, 6, 9). In humans, the intrahepatic biliary epithelium has been divided based upon duct diameter size (1, 6, 9): small bile ductules ( 800 μm) ducts (1, 5, 6, 9). Small ductules are lined by four to five cholangiocytes, which are characterized by the presence of a basement membrane, tight junctions between cells and microvilli projecting into the bile duct lumen (5, 9, 20). Small bile ducts join into interlobular ducts ranging from 20-100 μm in cross-sectional diameter (5, 6, 9, 20). In large bile ducts, cholangiocytes are larger and more columnar in shape (6, 9, 20). Similar to humans, a number of in situ (in liver sections) and in vitro (in purified small and large cholangiocytes and isolated small and large intrahepatic bile duct units) studies have demonstrated that the rat intrahepatic biliary epithelium is morphologically heterogeneous (7, 8, 14).