Journal Article

Liver Progenitor Cell Line HepaRG Differentiated in a Bioartificial Liver Effectively Supplies Liver Support to Rats with Acute Liver Failure

van der Hoeven, Tessa V., Oude Elferink, Ronald P. J., Hoekstra, Ruurdtje, Lamers, Wouter H., Maas, Martinus A. W., Nibourg, Geert A. A., Ruiter, An F. C., Chamuleau, Robert A. F. M., van Gulik, Thomas M.

2012

Overview

A major roadblock to the application of bioartificial livers is the need for a human liver cell line that displays a high and broad level of hepatic functionality. The human bipotent liver progenitor cell line HepaRG is a promising candidate in this respect, for its potential to differentiate into hepatocytes and bile duct cells. Metabolism and synthesis of HepaRG monolayer cultures is relatively high and their drug metabolism can be enhanced upon treatment with 2% dimethyl sulfoxide (DMSO). However, their potential for bioartificial liver application has not been assessed so far. Therefore, HepaRG cells were cultured in the Academic Medical Center bioartificial liver (AMC-BAL) with and without DMSO and assessed for their hepatic functionality in vitro and in a rat model of acute liver failure. HepaRG-AMC-BALs cultured without DMSO eliminated ammonia and lactate, and produced apolipoprotein A-1 at rates comparable to freshly isolated hepatocytes. Cytochrome P450 3A4 transcript levels and activity were high with 88% and 37%, respectively, of the level of hepatocytes. DMSO treatment of HepaRG-AMC-BALs reduced the cell population and the abovementioned functions drastically. Therefore, solely HepaRG-AMC-BALs cultured without DMSO were tested for efficacy in rats with acute liver failure (n = 6). HepaRG-AMC-BAL treatment increased survival time of acute liver failure rats ∼50% compared to acellular-BAL treatment. Moreover, HepaRG-AMC-BAL treatment decreased the progression of hepatic encephalopathy, kidney failure, and ammonia accumulation. These results demonstrate that the HepaRG-AMC-BAL is a promising bioartificial liver for clinical application.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Ammonia / Animals / Apolipoprotein A / Apolipoproteins / Artificial organs / Bile ducts / Biology / Cell cycle / Cell death / Cell Differentiation / Cytochrome / Cytochrome P450 / Dimethyl sulfoxide / Drug metabolism / Encephalopathy / Epidermal growth factor / Failure / Gene expression / Genomes / Health care facilities / Hepatic encephalopathy / Hepatocytes / Inflammation / Laboratories / Lactic acid / Liver / Liver - pathology / Liver diseases / Liver failure / Liver Failure, Acute - pathology / Liver Failure, Acute - therapy / Liver transplants / Liver, Artificial / Medical schools / Medicine / Metabolism / Monomolecular films / Progenitor cells / Rats / Renal failure / Reverse Transcriptase Polymerase Chain Reaction / Rodents / Stem Cells - pathology / Surgery / Transcription