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Elucidating the molecular mechanisms involved in the differentiation of stem cells to hepatic cells is critical for both understanding normal developmental processes as well as for optimizing the generation of functional hepatic cells for therapy. We performed  in vitro  differentiation of mouse embryonic stem cells (mESCs) with a null mutation in the homeobox gene  Hhex  and show that  Hhex   -/-   mESCs fail to differentiate from definitive endoderm (Sox17 + /Foxa2 + ) to hepatic endoderm (Alb + /Dlk + ). In addition, hepatic culture elicited a >7-fold increase in  Vegfa  mRNA expression in  Hhex   -/-   cells compared to  Hhex   +/+   cells. Furthermore, we identified VEGFR2 + /ALB + /CD34 -  in early  Hhex   +/+   hepatic cultures. These cells were absent in  Hhex   -/-   cultures. Finally, through manipulation of  Hhex  and  Vegfa  expression, gain and loss of expression experiments revealed that  Hhex  shares an inverse relationship with the activity of the  Vegf  signaling pathway in supporting hepatic differentiation. In summary, our results suggest that  Hhex  represses  Vegf  signaling during hepatic differentiation of mouse ESCs allowing for cell-type autonomous regulation of  Vegfr2  activity independent of endothelial cells.

Hhex Is Necessary for the Hepatic Differentiation of Mouse ES Cells and Acts via Vegf Signaling