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Am J Physiol Gastrointest Liver Physiol 295: G305-G312, 2008. First published June 12, 2008; doi:10.1152/ajpgi.90229.2008
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LIVER AND BILIARY TRACT

Interaction of CD44 and hyaluronic acid enhances biliary epithelial proliferation in cholestatic livers

Yao He,1 Gordon D. Wu,1 Tomohito Sadahiro,1 Sang-Ik Noh,1 Hong Wang,1 Dodanim Talavera,1 Haimei Wang,1 John M. Vierling,2 and Andrew S. Klein1

1Comprehensive Transplant Center, Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, California; 2Department of Hepatology, Baylor College of Medicine, Houston, Texas

Submitted 10 March 2008 ; accepted in final form 8 June 2008

Biliary epithelia express high levels of CD44 in hepatobiliary diseases. The role of CD44-hyaluronic acid interaction in biliary pathology, however, is unclear. A rat model of hepatic cholestasis induced by bile duct ligation was employed for characterization of hepatic CD44 expression and extracellular hyaluronan distribution. Cell culture experiments were employed to determine whether hyaluronan can regulate cholangiocyte growth through interacting with adhesion molecule CD44. Biliary epithelial cells were found to express the highest level of CD44 mRNA among four major types of nonparenchymal liver cells, including Kupffer, hepatic stellate, and liver sinusoidal endothelial cells isolated from cholestatic livers. CD44-positive biliary epithelia lining the intrahepatic bile ducts were geographically associated with extracellular hyaluronan accumulated in the portal tracts of the livers, suggesting a role for CD44 and hyaluronan in the development of biliary proliferation. Cellular proliferation assays demonstrated that cholangiocyte propagation was accelerated by hyaluronan treatment and antagonized by small interfering RNA CD44 or anti-CD44 antibody. The study provides compelling evidence to suggest that proliferative biliary epithelia lining the intrahepatic bile ducts are a prime source of hepatic CD44. CD44-hyaluronan interaction, by enhancing biliary proliferation, may play a pathogenic role in the development of cholestatic liver diseases.

bile duct ligation; biliary epithelial cell; small interfering RNA


Address for reprint requests and other correspondence: G. Wu, Director of Transplant Immunobiology Laboratory at Comprehensive Transplant Ctr., Cedars-Sinai Medical Center, 8700 Beverly Blvd., Los Angeles, CA 90048 (e-mail: gordon.wu{at}cshs.org)






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