Fig. 7. Model of trophoblast stem cell differentiation: the oxygen-independent role of HIF-regulated HDAC activity. In the presence of FGF4, TS cells are maintained in a replicative pluripotent state. Upon growth factor withdrawal, wild-type TS cells differentiate along the pathway that leads to giant cell formation. Although portrayed as a linear sequence, it is also possible that this differentiation pathway bifurcates, with either spongiotrophoblasts or trophoblast giant cells being produced. HIF activity suppresses generation of chorionic trophoblasts and syncytiotrophoblasts, whereas HDAC and HSP90 activity is required for trophoblast giant cell formation in vitro. In support of this model, Arnt-null TS cells predominantly differentiated into chorionic trophoblasts and syncytiotrophoblasts, with the HDAC inhibitor TSA having similar effects. Interestingly, the HSP90 inhibitor geldanamycin selectively inhibited trophoblast giant cell differentiation.