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- Heterogeneity of the intrahepatic biliary epithelium

In this review, we have summarized the findings demon-strating that the intrahepatic biliary epithelium is heterogeneous regarding: (1) morphological characteristics, vascularization and innervation; (2) secretory activity in response to gastrointestinal hormones/peptides, nerve receptor agonists and bile salts; and (3) apoptotic and proliferative responses to liver injury/toxins and gastrointestinal hormones/peptides. Specifically, the intrahepatic biliary epithelium is formed by bile ducts of different sizes with small ducts lined by small cholangiocytes, whereas larger ducts are lined by larger cholangiocytes[12-14]. Following a general background on cholangiocyte functions, we discussed the in vivo and in vitro experimental models that allowed us to demonstrate that the biliary epithelium is morphologically and functionally heterogeneous. Following a brief review on the heterogeneous distribution of non-transport related proteins, we discussed the secretory functions of small and large cholangiocytes. While large cholangiocytes secrete water and electrolytes[12,13,48] by changes in cAMP/PKA/CFTR/Cl-/HCO3-, small cholangiocytes may secrete bile by a transduction pathway (different from that observed in large cholangiocytes)[12,13,48] involving activation of IP3/Ca2+/PKC. We have presented data demonstrating that small and large cholangiocytes differentially proliferate or are damaged in response to liver injury/toxins. Small and large ducts also differ regarding the proliferative and apoptotic responses to liver injury/toxins[2,71,73]. We propose that activation of the Ca2+-dependent NFAT stimulates the proliferation of small cholangiocytes, whereas neural/hormonal-dependent activation of the cAMP-dependent CREB stimulates the proliferation of large cholangiocytes.  In the last part of the review, we have briefly outlined the heterogeneity of the biliary epithelium in relationship to chronic cholestatic liver diseases targeting different sized ducts.
Future Perspectives
The concept that the biliary epithelium is functionally heterogeneous is clinically relevant since in chronic cholestatic liver diseases cholangiocyte proliferation/damage is an event restricted to a specific duct size. Further studies are needed for understanding the pathophysiology of small cholangiocytes in the overall contribution of the functions of the biliary epithelium. However, some preliminary studies from our laboratory suggest that small cholangiocytes secrete bile (by a IP3/Ca2+/PKC-dependent mechanism) and proliferate by activation of the Ca2+-dependent transcription factor, NFAT. Further studies are necessary to evaluate the role of the nervous system in the regulation of the heterogeneous secretory, apoptotic and proliferative responses of different sized bile ducts to gastrointestinal hormones, injury/toxins and viruses. Since PBP proliferation is observed only in large proliferating cholangiocytes from BDL rats, we propose that blood supply and circulating factors (e.g., vascular endothelial growth factor and placental growth factor) may be important in the regulation of the heterogeneous response of cholangiocytes to liver injury/toxins.

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