Gradient oxygen differentially regulates trophoblast giant cell differentiation

Abstract

Preeclampsia is a condition associated with approximately 7–10% of all pregnancies and is known to induce maternal hypertension, increasing the risk for IUGR and premature birth. An important feature of preeclampsia is altered differentiation of invading placental trophoblast cells. While early trophoblast development takes place in severe hypoxia, trophoblast cells encounter an increasing oxygen gradient as they migrate and invade the maternal tissues. In this study, we examined the functional, morphological, and molecular differentiation of Rcho-1 trophoblast cells under a range of oxygen concentrations. Severe hypoxia maintained the expression of trophoblast stem cell marker Id2 and inhibited the induction of palladin and CSH1 protein, and formation of stress fibers. Moderate hypoxia, however, was unable to sustain Id2 expression and low levels of palladin protein induction and stress fiber formation was observed. HIF-1alpha, a potential transcriptional mediator in low oxygen conditions exhibited constitutive mRNA expression under all oxygen conditions. In contrast, HIF-1alpha protein levels and reporter activity decreased with increasing oxygen levels. These results suggest that an oxygen gradient differentially modulates aspects of trophoblast giant cell differentiation in a stepwise fashion and that HIF-1alpha may play a key role in oxygen’s inhibition of trophoblast differentiation. This work was supported by NICHD, National Institute of Health Grant (HD045750, T.L.B).