Immunohistochemical evidence for hepatic progenitor cells in liver diseases

Abstract

Background/Aim: Proliferative bile ductular reactions occur in a variety of liver diseases in humans. It is a matter of debate whether such reactions result from progenitor cell proliferation with biliary and hepatocytic differentiation, versus biliary metaplasia of damaged hepatocytes. We investigated bile ductular reactions in liver diseases, paying particular attention to the presence of cells with intermediate (hepatocytic/ biliary) features (oval-like cells). Methods: Five specimens each were selected of submassive hepatic necrosis and cirrhosis due to hepatitis B, hepatitis C, autoimmune hepatitis, alcohol injury, primary biliary cirrhosis and primary sclerosing cholangitis. Immunohistochemical stains were performed for biliary markers (cytokeratins [CKs] 7 and 19), as well as hepatocytic markers (HepParl and alpha-fetoprotein [AFP]) in sequential sections. The degree of staining of each cell type (biliary, hepatocytic, intermediate) was graded semiquantitatively. Results: Hepatocytes always stained diffusely for HepParl, occasionally for CK7, and rarely for CK19. Biliary cells were always diffusely positive for CK7 and CK19, and rarely for HepParl. Intermediate cells were identi®ed in all cases and showed widespread staining for both HepParl and CK7, and less commonly for CK19. AFP was not expressed in any cell type. The morphologic and immunohistochemical features of bile ductular reactions were similar in the different diseases. Conclusions: Proliferating hepatic parenchymal cells with intermediate (hepatocytic/biliary) morphologic features and combined immunophenotype can be identi®ed in a variety of acute and chronic liver diseases. The similarity of bile ductular reactions among chronic hepatitic, alcoholic and biliary diseases suggests that they result from proliferation of oval-like progenitor cells.

Identification of hepatocytic and bile ductular cell lineages and candidate stem cells in bipolar ductular reactions in cirrhotic human liver

“…[17][18][19][20] Oval cells are commonly found in pathological structures called "ductular reactions" (DRs). [21][22][23][24][25] Some investigators have suggested that oval cells in human liver disease should be referred to as "intermediate hepatobiliary cells" because they may not be equivalent to oval cells in rodents. 21 A common characteristic of these human diseases (also common with rodent experimental systems) is that regeneration of the resident hepatocyte population is severely limited.…”

Pluripotent plasticity of stem cells and liver repopulation

“…28,29 The basic reaction types of the liver alterations can be divided into well-defined categories: adaptive changes, degeneration and intracellular storage, cell death (necrosis/ apoptosis), inflammation, fibrosis, and structural reorganization, as well as regeneration/proliferation (cirrhosis). 29 Apoptosis occurs in several liver diseases, with a striking form appearing to be the Councilman-like body seen in alcoholic but also in viral hepatitis. It may have role in the pathogenesis of cholestasis, biliary atresy, the ''vanishing bile duct syndrome,'' and alcoholic liver injury.…”

“…The regenerating nodules and accompanying fibrosis interfere with blood flow through the liver and result in portal hypertension, hepatic insufficiency, jaundice, and ascites. [28][29][30] Primary biliary cirrhosis is an autoimmune liver disease that predominantly affects women and is characterized by chronic progressive destruction of small intrahepatic bile ducts with portal inflammation and subsequent fibrosis. The serological hallmark is the presence of antimitochondrial antibodies, which are found in 95% of patients.…”

“…32 Studies on liver regeneration have led to the recognition of hepatic stem cells role in the healing process. 10,29 These cells of ''oval'' morphologic appearance are built up of a primitive structure, making them suitable for this task. Ductular proliferation originating from hepatic stem cells can mostly be recognized in three disease groups: liver regeneration following massive or sub-massive liver necrosis, ductular proliferation without liver insufficiency, and tumorous liver diseases.…”

“…28 Successful application of stem cell-associated therapies in man will be closely related with patient risk transplantation profiles, stringent indications, long-term patient outcomes, and will be determined by cost-benefit efficacy. 28,29 IN THE FUTURE In the future, pluripotent plasticity of stem cells will open a variety of clinical application strategies for the treatment of tissue injuries, degenerated organs, and body components. Clinical application of hepatocyte transplantation is limited by good quality donor livers for the isolation of cells, independently from their mesenchymal or hematopoietic origin.…”