Heterogeneity of the intrahepatic biliary epithelium

Figure 1 [Top] Isolation of small (A), approximately 8 μm diameter] and large (B), approximately 14 μm diameter] cholangiocytes from small and large ducts, respectively, from normal rats. Small and large cholangiocytes were purified by counterflow elutriation followed by immunoaffinity purification. Original magn., × 625. Reproduced with permission from Ref[12]. [Bottom] Isolation of small (C) and large (D) IBDU from normal rat liver. Small (< 15 μm in diameter) and large (> 15 μm in diameter) IBDU were pruned off from large ducts by a nitrogen pulsed dye laser and subsequently separated (D) by picking up IBDU with a micromanipulator micropipet. Original magnification × 2000. Reproduced with permission from Ref 13.

Figure 2 Measurement of H₃ histone gene expression in small and large cholangiocytes from 1-wk BDL rats and 1-wk BDL rats treated with CCl₄ or mineral oil. H₃ histone gene expression in large cholangiocytes decreased on d 2 before returning to control values on d 7 after CCl₄ treatment. H₃ histone gene expression (which was absent in small cholangiocytes from BDL rats) was expressed by small cholangiocytes on d 1 and 2 before returning to control undetectable values on d 7 after CCl₄ treatment. Administration of mineral oil to 1-wk BDL rats did not alter H₃ histone gene expression in large cholangiocytes. The message for H₃ histone gene was absent in small cholangiocytes from oil-treated rats. Comparability of RNA used was assessed by hybridization for GAPDH (housekeeping gene). Autoradiograms were quantified by densitometry. Densitometric values are means of 2 experiments. Reproduced with permission from Ref 50.

Figure 3 Working model for the heterogeneity of the intrahepatic biliary epithelium. The model proposes that: (1) bile ducts are morphologically heterogeneous with small ducts lined by small cholangiocytes and large ducts lined by large cholangiocytes; (2) small and large ducts similarly express both γ-GT and cytokeratin-19; and (3) large (but not small) ducts express the secretin and somatostatin receptor, CFTR and Cl^-/HCO₃^- and respond physiologically to these two hormones. The model also shows that following BDL, only large cholangiocytes proliferate and that a single dose of CCl₄ induces damage and loss of large duct function, whereas small cholangiocytes (resistant to CCl₄) de novo proliferate and secrete to compensate for the loss of large duct function. Reproduced with permission from Ref. 73.