HYPOXIA ALTERS EARLY GESTATION HUMAN CYTOTROPHOBLAST DIFFERENTIATION INVASION IN-VITRO AND MODELS THE PLACENTAL DEFECTS THAT OCCUR IN PREECLAMPSIA

During normal human pregnancy a subpopulation of fetal cytotrophoblast stem cells differentiate and invade the uterus and its arterioles. In the pregnancy disease preeclampsia, cytotrophoblast differentiation i s abnormal and invasion is shallow. Thus, the placenta is relatively h ypoxic. We investigated whether lowering oxygen tension affects cytotr ophoblast differentiation and invasion. Previously we showed that when early gestation cytotrophoblast stem cells are cultured under standar d conditions (20% O-2) they differentiate/invade, replicating many asp ects of the in vivo process. Specifically, the cells proliferate at a low rate and rapidly invade extracellular matrix (ECM) substrates, a p henomenon that requires switching their repertoire of integrin cell-EC M receptors, which are stage-specific antigens that mark specific tran sitions in the differentiation process. In this study we found that lo wering oxygen tension to 2% did not change many of the cells' basic pr ocesses. However, there was a marked increase in their incorporation o f [H-3]thymidine and 5-bromo-2'-deoxyuridine (BrdU). Moreover, they fa iled to invade ECM substrates, due at least in part to their inability to completely switch their integrin repertoire. These changes mimic m any of the alterations in cytotrophoblast differentiation/invasion tha t occur in preeclampsia, suggesting that oxygen tension plays an impor tant role in regulating these processes in vivo.