Regulation of cholangiocyte proliferation

Intrahepatic bile duct epithelial cells (i.e., cholangiocytes) are the targ et cells of chronic cholestatic liver diseases (i.e., cholangiopathies), wh ich makes these cells of great interest to clinical hepatologists. This rev iew will focus on "typical" cholangiocyte proliferation, whereas "atypical" (extension of cholangiocyte proliferation into parenchyma), and premaligna nt "oval" cell proliferation are reviewed elsewhere. The bile duct ligated (BDL) rat model, where most of the known mechanisms of cholangiocyte prolif eration have been illustrated, was the first and remains the prototype anim al model for "typical" cholangiocyte proliferation Following a short overvi ew of cholangiocyte functions, we briefly discuss the: (i) in vivo models [ i.e., BDL (Fig. 1 and 3), chronic alpha -naphthylisothiocyanate (ANIT) or b ile acid feeding (Fig. 2), acute carbon tetrachloride (CCl4) feeding and pa rtial hepatectomy; and (ii) in vitro experimental tools [e.g., purified cho langiocytes and isolated intrahepatic bile duct units (IBDU)] that are key to the understanding of the mechanisms of "typical" cholangiocyte growth. I n the second part of the review we discuss a number of potential factors or conditions [e.g., gastrointestinal hormones, nerves, estrogens, blood supp ly, and growth factors] as well as the intracellular mechanisms [e.g., aden osine 3',5'-monophosphate (cAMP), and protein kinase C (PKC)] that may regu late "typical" cholangiocyte hyperplasia.