Reversal of mouse hepatic failure using an implanted liver-assist device containing ES cell-derived hepatocytes

Severe acute liver failure, even when transient, must be treated by transplantation and lifelong immune suppression. Treatment could be improved by bioartificial liver ( BAL) support, but this approach is hindered by a shortage of human hepatocytes. To generate an alternative source of cells for BAL support, we differentiated mouse embryonic stem (ES) cells into hepatocytes by coculture with a combination of human liver nonparenchymal cell lines and fibroblast growth factor- 2, human activin A and hepatocyte growth factor. Functional hepatocytes were isolated using albumin promoter - based cell sorting. ES cell - derived hepatocytes expressed liver- specific genes, secreted albumin and metabolized ammonia, lidocaine and diazepam. Treatment of 90% hepatectomized mice with a subcutaneously implanted BAL seeded with ES cell - derived hepatocytes or primary hepatocytes improved liver function and prolonged survival, whereas treatment with a BAL seeded with control cells did not. After functioning in the BAL, ES cell - derived hepatocytes developed characteristics nearly identical to those of primary hepatocytes.