Development of stabilin2+ endothelial cells from mouse embryonic stem cells by inhibition of TGFβ/activin signaling

To understand the endothelial cell (EC) development, arterial, venous, and lymphatic EC (LEC) have been successfully induced from embryonic stem cells (ESC). However, tissue-specific EC, such as hepatic sinusoidal EC (HSEC), have never been generated from ESC. Based on the findings that TGFβ/activin signaling negatively regulates differentiation of both LEC and HSEC, and that HSEC and LEC are distinguishable by the expression of marker genes, we assessed the role of TGFβ/activin signaling in EC development from ESC. Here we show that the inhibition of TGFβ/activin signaling by a TGFβ receptor I (TGFβRI) kinase inhibitor increased the expression of Lyve1 and stabilin2 but not podoplanin in CD31+CD34+ EC derived from ESC. EC generated by the inhibition of TGFβRI signaling also exhibited stronger endocytic activity than control EC, indicating that their phenotype is similar to fetal HSEC. Our results reveal that TGFβ/activin signaling negatively regulates the early events of HSEC differentiation.