Atypical ductular proliferation and its inhibition by transforming growth factor beta 1 in the 3,5-diethoxycarbonyl-1,4-dihydrocollidine mouse model for chronic alcoholic liver disease

Many acute and chronic liver diseases are often associated with atypical du ctular proliferation (ADP). These ADPs have gained increasing interest sinc e a number of recent observations suggest that ADPs may represent progenies of the putative liver stem cell compartment. In this study, we show that f eeding mice with 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) results in persistent proliferation of primitive ductules with poorly defined lumens. Similar to oval cell proliferation in other rodent models as well as in va rious human liver diseases, DDC-induced ADP originated from the portal trac t, spread into the hepatic lobule, and was associated closely with appearan ce of hepatocytes harboring an antigen (A6), which normally is expressed in biliary epithelium. Furthermore, DDC treatment severely inhibited the rege nerative capacity of mice after partial hepatectomy. The development of ADP was selectively blocked in DDC-fed TGF-beta 1 transgenic mice producing ac tive TGF-beta 1 in the liver and no accumulation of new hepatocytes express ing the A6 antigen was observed. Moreover, the transforming growth factor p i (TGF-beta 1) transgenic mice did not survive beyond 3 weeks from starting the DDC-containing diet. The results suggest that persistent activation of the hepatic stem cell compartment is essential for liver regeneration in t he DDC model and that active TGF-beta 1 may negatively control activation o f stem cells in the liver. These data further emphasize the relevance of th e DDC model as an experimental tool for studying chronic liver diseases.