American Society for Investigative Pathology, February 2011, Vol 3, No. 1

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Hot off the AJP Press!

This page features articles recently published in The American Journal of Pathology (AJP) and/or The Journal of Molecular Diagnostics (JMD).

Disparate cellular basis of improved liver repair in beta-catenin-overexpressing mice after long-term exposure to 3,5-diethoxycarbonyl-1,4-dihydrocollidine.
Thompson MD, Awuah P, Singh S, Monga SP.
From the Department of Pathology, University of Pittsburgh, School of Medicine, Pittsburgh, Pennsylvania 15216, USA.
Am J Pathol. 2010 Oct;177(4):1812-22.

A synopsis written by co-author and ASIP trainee Dr. Michael Thompson under the direction of Dr. Paul Monga at the University of Pittsburgh School of Medicine Department of Pathology.

As the search continues for alternatives to embryonic stem cells for cellular therapies, adult progenitor cells have been a primary focus in multiple organs. This is particularly true for the liver, as alternatives to hepatic transplantation are needed. The adult liver progenitor cell, or oval cell, has been an area of great debate over the last many years. The ability of the resident parenchymal cells of the liver, namely the hepatocytes and biliary epithelial cells, to efficiently proliferate despite being terminally differentiated and thus repopulate the liver following transplantation is well known, questioning the need for a true progenitor cell in the liver. Despite this, studies have shown that in the setting of significant injury beyond the repair capabilities of the mature resident cells, a hepatic progenitor is called into action in the regeneration process. While it is clear that such cells exist albeit scarce in a healthy liver, their primary location and regulatory signals responsible for their maintenance, expansion, and differentiation, still remains to be conclusively defined. Indeed, several progenitor niches have been reported suggesting that a heterogeneous progenitor population may exist. In fact variability in progenitor cell response has been evident following diverse experimental stimuli. Furthermore, oval cells are bipotential in nature as they express markers specific to both hepatocytes and cholangiocytes, and in vitro and in vivo studies have reported the ability of these cells to differentiate into either epithelial cell type.

Generally, the oval cell population is quiescent and only proliferates at times when the hepatocytes and cholangiocytes themselves are impaired or overwhelmed. Not surprisingly oval cell activation is observed in conditions associated with chronic liver injury and development of hepatocellular carcinoma (HCC) such as chronic viral hepatitis, alcoholic liver disease, and nonalcoholic fatty liver disease. Various studies have reported on the presence of markers of progenitor cells or oncofetal proteins in HCC, as well as the presence of progenitors in small dysplastic foci and hepatic adenomas. Given such association with liver cancer, great interest lies in identification of the molecular characteristics of this cell population for targeted therapy.

In an attempt to decipher the molecular mechanisms involved, multiple animal models have been developed for oval cell activation. One model commonly used in mice is the DDC diet model. This model has been used for studying Mallory body formation for about 30 years, but only gained interest as an oval cell model in the last decade. Given that the DDC diet protocol replicates many of the features of chronic cholangiopathies; it is also a valuable model for the investigation of the mechanism of biliary disease and the subsequent reparative process. Based on the role of Wnt/β-catenin pathway in liver development and stem cell biology in general, we conducted a study to determine its role in oval cell response. We previously reported a significant co-localization of the ductular and oval cell marker A6 and β-catenin especially after feeding DDC diet in mice. Moreover, ablation of β-catenin in the liver in this model led to a blunted oval cell response indicating that β-catenin has a role in optimum induction and expansion of oval cells. In the current study, we examine whether excess β-catenin in transgenic (TG) mice would provide any increase in the oval cell response or any reparative advantage in response to DDC diet induced injury. To our surprise, we observed no differences in appearance or numbers of oval cells after DDC administration. However, it was clear that an additional population of A6 positive cells, which had the morphological appearance of hepatocytes, was more abundant in the TG animals. These "atypical hepatocytes" in the TG livers was observed after 14 and 28 days, coinciding with an increase in proliferating cell nuclear antigen-positive hepatocytes. Intriguingly, after chronic DDC administration for 150 days, a significant portion of the TG liver was populated by atypical hepatocytes. Coincidently, we observed an improvement in intrahepatic cholestasis as seen by decreases in both serum bilirubin and alkaline phosphatase levels, indicating an overall improvement in hepatic repair. To validate this finding, we performed recovery studies where mice were exposed to DDC for 4 weeks followed by reinstitution of normal chow. This experiment showed decreases in alkaline phosphatase, atypical ductular proliferation, and periportal inflammation compared with wild-type animals, verifying improved biliary repair in TG livers. Thus, we report a potential role of β-catenin in liver repair, especially in enhancing the resolution of intrahepatic cholestasis after DDC injury. β-Catenin activation may have prognostic and therapeutic implication