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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.
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