WNT and BMP signaling are both required for hematopoietic cell development from human ES cells.

Pluripotent human embryonic stem (hES) cells are capable of generating a variety of mature cell types, including hematopoietic cells in vitro. However, the precise signaling mechanisms that regulate hematopoietic cell development from hES cells are still poorly documented. Here we demonstrate that hemoangiogenic cells derived from hES cells are defined by their high-level expression of KDR and low-level expression of PDGFRalpha (KDR(+)PDGFRalpha(lo)), and that the generation of such cells from hES cells is significantly elevated by the addition of WNT3a or BMP4 during differentiation. The addition of WNT3a caused the induction of both hemogenic and angiogenic activities, and the addition of BMP4 preferentially increased angiogenic activity, all enriched in the KDR(+)PDGFRalpha(lo) cell fraction. Interestingly, WNT3a stimulation of hemoangiogenic cell genesis was virtually abolished in the presence of a BMP inhibitor. On the other hand, the BMP4-induced angiogenic cell genesis was suppressed by coaddition of a WNT inhibitor. Thus, WNT and BMP signaling coordinately direct the differentiation of hES cells into KDR(+)PDGFRalpha(lo) hemoangiogenic cells.