Thomas Brown (Advisor), Paula Bubulya (Committee Member), Michael Leffak (Committee Member), Robert Putnam (Committee Member), Christopher Wyatt (Committee Member)
Doctor of Philosophy (PhD)
Early embryonic development occurs under low oxygen levels. The placenta is an organ transiently formed during pregnancy and plays a crucial role during development of the embryo. Alterations in the placental structure or function have been associated with the pathologies such as preeclampsia in humans. In mammals, the hypoxia inducible factor (HIF) transcription factors have been identified as the major regulators of cellular responses in low oxygen. In the current study, we investigated the effects of low oxygen on the differentiation of trophoblast stem cells, lineage committed trophoblast giant cells and labyrinthine lineage-committed cells. We examined the effects of an oxygen-insensitive form of HIF-1 alpha on the differentiation of lineage-committed trophoblast giant cells. Using a novel lentivirus-mediated, placental-specific gene expression strategy, we investigated the effect of prolonged HIF-1 alpha on placental and embryonic development in vivo. Our studies suggest that low oxygen inhibits differentiation of trophoblast cells and affects several placental lineages. The expression of the oxygen-insensitive form of HIF-1 alpha inhibited the molecular, morphological and functional differentiation of trophoblast giant cells. Placental specific expression of the oxygen-insensitive form of HIF-1 alpha, also led to significant alterations in placental morphology that mimic the pathology of two pregnancy-related conditions in humans, preeclampsia and intrauterine growth restriction (IUGR). Our studies show that HIF-1 alpha is a master regulator of trophoblast differentiation and placental development.
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