Stem Cell-based Modeling of Placental Defects associated with Early-Onset Preeclampsia

Project Summary/Abstract Preeclampsia (PE) is a multifactorial pregnancy syndrome that affects up to 10% of pregnancies worldwide, and is defined by new onset of hypertension and proteinuria or end-organ dysfunction appearing after 20 weeks of gestation. Although the well-accepted underlying pathophysiology of this disease involves both maternal and fetal/placental factors, the symptoms resolve following the delivery of the placenta pointing to the importance of placental involvement in this disease. The placental histological phenotype of PE is known to have a wide range of lesions. Maternal vascular malperfusion (MVM), one of the predominant placental injuries associated with PE, is known for abnormal syncytiotrophoblast and extravillous trophoblast differentiation and function, with some cases overlapping with fetal vascular malperfusion (FVM). However, the detailed underlying molecular and cellular pathophysiology associated with PE placenta showing MVM, with or without FVM, is not well-understood. Therefore, we have set the following three aims in this proposal, combining a novel trophoblast modeling system, the molecular characterization of the placenta, and evaluate influence of mesenchymal stem/stromal cells (MSC) at the chorionic villi and elucidate the detailed mechanism associated with this pathology. Aim 1 will identify the optimal stem cell-based method to study abnormal trophoblast differentiation in PE placenta. Aim 2 will focus on in-depth characterization of PE- MVM placentas with or without FVM, and bank and characterize the cellular phenotype of each MVM subtypes of umbilical cord-derived MSCs. Aim 3 will evaluate the trophoblast-MSC crosstalk within the chorionic villi of PE placentas with different MVM-subtypes. The successful completion of this proposal will establish subtype-specific cell-based models of PE, providing effective tools for identifying diagnostic biomarkers and therapeutic targets for each sutypes, leading us to the better pregnancy care for woman and babies.