Background and Aims: While the lobular heterogeneity of hepatocytes is established, limited data suggest that bile duct epithelial cells, or cholangiocytes, are heterogeneous along the normal intrahepatic biliary tree. Thus, we tested the hypothesis that cholangiocytes are structurally and functionally heterogeneous in the biliary tract of normal rats. Methods: A series of in situ and in vitro experiments was performed in normal rats using complementary morphometric, molecular, and functional approaches. Results: In situ morphometry showed that (1) intrahepatic bile ducts are heterogeneous in external diameter (5-200 μm); (2) individual cholangiocytes lining bile ducts are heterogeneous in area (3-80 μm2); and (3) a significant relationship exists between bile duct diameter and cholangiocyte area. Using a novel approach developed by us, we isolated three subpopulations of small, medium, and large cholangiocytes and compared them at the molecular and functional level. The expression of two cholangiocyte-specific genes (γ- glutamyl transpeptidase and cytokeratin 19) was similar among the three subpopulations. In contrast, secretin receptor, Cl-/HCO3 exchanger, and cystic fibrosis transmembrane conductance regulator messenger RNAs were differentially expressed, being present in medium and large but not small cholangiocytes. At the functional level, adenosine 3', 5'-cyclic monophosphate and intracellular pH responses and Cl-/HCO3 exchanger activity was enhanced by secretin in medium and large but not small cholangiocytes. Conclusions: These data indicate that cholangiocytes are morphologically and functionally heterogeneous along the normal intrahepatic biliary tree and suggest that secretin-regulated transport of water and electrolytes occurs principally in medium and large ducts.
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