Morphological, molecular, and functional heterogeneity of cholangiocytes from normal rat liver.
OBJECTIVE
While the lobular heterogeneity of hepatocytes is established, limited data suggest that bile duct epithelial cells, of 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 mum); (2) individual cholangiocytes lining bile ducts are heterogeneous in area (3-80 mum2); 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 (gamma-glutamyl transpeptidase and cytokeratin 19) was similar among the three subpopulations. In contrast, secretion receptor, Cl-/HCO3- exchanger, and cystic fibrosis transmembrane conductance regulator messenger RNAs were differentially expressed, being present on 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 secretion 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 secretion-regulated transport of water and electrolytes occurs principally in medium and large ducts.
Alpini
G
G
Department of Biochemistry and Molecular Biology, Mayo Medical School, Rochester, Minnesota, USA.
Roberts
S
S
Kuntz
S M
SM
Ueno
Y
Y
Gubba
S
S
Podila
P V
PV
LeSage
G
G
LaRusso
N F
NF
D000818:Animals; D017920:Antiporters / Q000235:genetics / Q000378:metabolism; D001653:Bile Ducts, Intrahepatic / Q000166:cytology* / Q000378:metabolism / Q000502:physiology; D027963:Chloride-Bicarbonate Antiporters; D000242:Cyclic AMP / Q000378:metabolism; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics; D004847:Epithelial Cells; D004848:Epithelium / Q000378:metabolism / Q000502:physiology; D015870:Gene Expression; D006863:Hydrogen-Ion Concentration; D007633:Keratins / Q000235:genetics; D008297:Male; D051381:Rats; D011916:Rats, Inbred F344; D043562:Receptors, G-Protein-Coupled; D011964:Receptors, Gastrointestinal Hormone / Q000235:genetics; D012633:Secretin / Q000494:pharmacology; D005723:gamma-Glutamyltransferase / Q000235:genetics
D017920:Antiporters; D027963:Chloride-Bicarbonate Antiporters; D043562:Receptors, G-Protein-Coupled; D011964:Receptors, Gastrointestinal Hormone; C029937:secretin receptor; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D012633:Secretin; D007633:Keratins; D000242:Cyclic AMP; D005723:gamma-Glutamyltransferase