Abstract
BackgroundInduction of stem cell differentiation toward functional hepatocytes is hampered by lack of knowledge of the hepatocyte differentiation processes. The overall objective of this project is to characterize key stages in the hepatocyte differentiation process.ResultsWe established a mouse embryonic stem (mES) cell culture system which exhibited changes in gene expression profiles similar to those observed in the development of endodermal and hepatocyte-lineage cells previously described in the normal mouse embryo. Transgenic mES cells were established that permitted isolation of enriched hepatocyte-lineage populations. This approach has isolated mES-derived hepatocyte-lineage cells that express several markers of mature hepatocytes including albumin, glucose-6-phosphatase, tyrosine aminotransferase, cytochrome P450-3a, phosphoenolpyruvate carboxykinase and tryptophan 2,3-dioxygenase. In addition, our results show that the up-regulation of the expression levels of hepatocyte nuclear factor-3α, -4α, -6, and CCAAT-enhancer binding protein-β might be critical for passage into late-stage differentiation towards functional hepatocytes. These data present important steps for definition of regulatory phenomena that direct specific cell fate determination.ConclusionThe mES cell culture system generated in this study provides a model for studying transition between stages of the hepatocyte development and has significant potential value for studying the molecular basis of hepatocyte differentiation in vitro.
Highlights
Induction of stem cell differentiation toward functional hepatocytes is hampered by lack of knowledge of the hepatocyte differentiation processes
embryoid bodies (EBs) = mouse embryonic stem (mES) cell populations generated from non-differentiated embryonic stem (ES) medium (NDESM) culture, ES = non-differentiated mES cells, N = mES cell populations generated from hepatocyte-inducing medium (HIM) culture, Number indicate days in culture]
Flow cytometry fractionation of hepatocyte-lineage cells from differentiated mES cell populations culture in HIM enhanced the derivation of cells of hepatocyte-lineage, it was clear that mES cell populations generated from this culture condition contained mixed cell types
Summary
Induction of stem cell differentiation toward functional hepatocytes is hampered by lack of knowledge of the hepatocyte differentiation processes. The overall objective of this project is to characterize key stages in the hepatocyte differentiation process. Liver failure is one of the major causes of morbidity and mortality worldwide [1]. The only effective treatment so far for acute and chronic liver failure is liver transplantation [2]. Hepatocyte transplantation therapy has emerged as an attractive alternative treatment for endstage liver disease [3,4,5]. To enhance the potential for this approach, hepatocyte transplantation therapy requires a renewable cell source of functional hepatocytes in vitro. One of the most promising potential sources of functional hepatocytes is from directed embryonic stem (ES) cell differentiation
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