Pathophysiology of Cholangiocyte Cilia

Primary cilia are ubiquitous organelles found in most mammalian tissues. Recent studies suggest that they play an important role in epithelial cells, functioning as mechano‐, chemo‐ and/or osmo‐sensors. Moreover, morphological and functional ciliary abnormalities contribute to the development of different pathological conditions, in particular to autosomal dominant and recessive polycystic kidney and liver disease. However, information regarding the functions of primary cilia, particularly in the liver, is limited and how cilia respond to environmental stimuli is still poorly understood. Cholangiocytes, the epithelial cells lining intrahepatic bile ducts, each possess an individual cilium (approximately 7 μm in length) extending from the apical membrane into the ductal lumen with a typical 9+0 axoneme structure. They are heterogeneous in length along the biliary tree; i.e., in the large bile ducts, cilia are 2–3 times longer than in small ones. The strategic location of cholangiocyte cilia extending into the bile duct lumen raises questions about their role in sensing and transducting mechanical, chemical and osmotic signals between molecules in bile and cholangiocytes. Thus, development of novel approaches to study and isolate primary cilia are essential to understand the functions of these organelles. In this presentation, we will review the novel models we have developed to study cholangiocyte cilia, including: isolated perfused bile ducts from rat and mouse; cultured rodent cholangiocyte cell systems to evaluate ciliogenesis and cystogenesis; rodent models of cystic kidney and liver disease; and cell biologic techniques to isolate cilia. The application of these in vitro and in vivo techniques to hepatic cyst formation and expansion will also be emphasized.