Two groups describe hepatic differentiation of mouse embryonic stem (ES) cells. Gouon-Evans et al. use knowledge of developmental pathways to produce immature hepatocytes that secrete albumin and store glycogen. Soto-Gutiérrez et al. show that ES cell-derived hepatocytes encapsulated in a bioartificial liver device are effective in treating mice with acute liver failure.
In order to generate an alternative source of cells for BAL support, American and Japanese scientist around Ira Fox and Naoya Kobayashi 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.
Reversal of mouse hepatic failure using an implanted liver-assist device containing ES cell–derived hepatocytes
Nature Biotechnology - 24, 1412 - 1419 (2006)
Valerie Gouon-Evans and co-workers present their findings concerning the role of BMP-4 for hepatic specification of mouse embryonic stem cell–derived definitive endoderm. When differentiated in the presence of activin A in serum-free conditions, mouse embryonic stem cells efficiently generate an endoderm progenitor population defined by the coexpression of either Brachyury, Foxa2 and c-Kit, or c-Kit and Cxcr4. Specification of these progenitors with bone morphogenetic protein-4 in combination with basic fibroblast growth factor and activin A results in the development of hepatic populations highly enriched (45–70%) for cells that express the -fetoprotein and albumin proteins. These cells also express transcripts of Afp, Alb1, Tat, Cps1, Cyp7a1 and Cyp3a11; they secrete albumin, store glycogen, show ultrastructural characteristics of mature hepatocytes, and are able to integrate into and proliferate in injured livers in vivo and mature into hepatocytes expressing dipeptidyl peptidase IV or fumarylacetoacetate hydrolase. Together, these findings establish a developmental pathway in embryonic stem cell differentiation cultures that leads to efficient generation of cells with an immature hepatocytic phenotype.
BMP-4 is required for hepatic specification of mouse embryonic stem cell–derived definitive endoderm
Nature Biotechnology - 24, 1402 - 1411 (2006)
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