The molecular orchestra of early placenta development Key determinants of maternal-fetal health

This dissertation investigates the molecular mechanisms underlying healthy and pathological early human placenta development. The placenta is essential for fetal growth and survival, mediating nutrient and gas exchange, hormone production, and immune protection. Disruptions in its formation can lead to complications such as preeclampsia and fetal growth restriction. These complications originate early in pregnancy, during the period when in healthy conditions trophoblast cells differentiate and establish the maternal–fetal interface. Using human trophoblast stem cells, trophoblast organoids, and first-trimester placental and decidual tissue, this work explores both fetal and maternal factors regulating trophoblast differentiation and invasion. The findings reveal that reduced fetal activity of the transcriptional coactivator EP300 impairs the formation of both syncytiotrophoblasts and extravillous trophoblasts, identifying EP300 as a key regulator of trophoblast lineage development. In addition, maternal excess of the pro-inflammatory cytokines IFN-α and TNF-α inhibit trophoblast invasion without affecting differentiation, offering insight into how maternal autoimmune conditions may predispose to placental dysfunction. Together, these results emphasize the need for balanced molecular signaling between fetal and maternal components to support normal placentation. Additional studies showed no adverse effects of the maternal immune response to COVID-19 mRNA vaccination on trophoblast development, reinforcing vaccine safety in pregnancy. Furthermore, analyses of alternative RNA splicing during trophoblast differentiation, and optimized methods for deriving patient-specific trophoblast stem cells, provide new hypotheses and tools for investigating regulatory pathways and disease mechanisms. Overall, this thesis highlights the intricate coordination required for placental development and its critical role in ensuring healthy pregnancy outcomes.