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The Role of BMP4 and Oxygen in Trophoblast Lineage Specification and Differentiation


Trophoblasts, the placental epithelial cells, provide the main structural and functional component of the placenta. They arise from the trophectoderm, the first lineage to be specified during embryogenesis. Trophectoderm lineage specification and the bulk of placental growth occur under low oxygen tension. In vivo, trophoblast precursor cells, known as cytotrophoblasts (CTB), proliferate under physiologic hypoxia and differentiate into invasive extravillous trophoblast (EVT). With increased oxygen tension, CTB differentiate into villous syncytiotrophoblast (STB). One major mechanism by which hypoxia regulates cell signaling is through hypoxia-inducible factor (HIF). Under hypoxia, the HIF complex is stabilized and acts as a transcription factor to mediate cellular responses to lower oxygen tension. Transgenic mice unable to form an intact HIF complex show abnormal trophoblast differentiation and placental function and die in mid-gestation. However, the role of HIF complex formation in human trophoblast differentiation has yet to be determined. For my dissertation, I explored how BMP4 signaling and oxygen tension affect trophoblast lineage specification and differentiation, and whether the effects are HIF-dependent. Using mouse trophoblast stem cells (mTSC), primary human trophoblast cells, and BMP4-treated human embryonic stem cells (hESC) as model systems, I found that, in mTSC, BMP4 inhibits differentiation into the trophoblast giant cell lineage, while in human, BMP4 decreases proliferation of CTB in explants and induces both initial trophoblast lineage specification and further differentiation in hESC. I also discovered that hypoxia promotes differentiation into EVT, and that this process is dependent on an intact HIF complex, in both primary cells and hESC. These results establish oxygen tension and HIF as a major regulator of trophoblast lineage-specific differentiation, but also confirm the utility of BMP4-treated hESC as a model which correctly recapitulates these processes in vitro. These data suggest that pluripotent stem cells may be useful in modeling human pregnancy complications such as recurrent miscarriage, preeclampsia, and intrauterine growth restriction, all of which have their roots in abnormal EVT differentiation and function.

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