While the underlying etiology of preeclampsia (a hypertensive disorder of pregnancy) is not known, the disease starts with shallow placentation and placental ischemia which in turn releases excess of anti-angiogenic proteins such as soluble fms-like tyrosine kinase 1 (sFLT1) in the mother's bloodstream that is responsible for the systemic maternal endothelial dysfunction. Self-renewing three-dimensional epithelial organoids that closely resemble the structure and physiology of the original organ have been successfully developed into various tissue types using human induced pluripotent stem cells (hiPSCs). However, organoids of the human placental trophoblasts using hiPSCs are yet to be generated. Our goal of this proposal is to generate trophoblast organoids from disease-specific hiPSCs to study preeclampsia pathogenesis and to screen for drugs as potential treatment targets. We will generate a new model of trophoblast organoid using hiPSCs, replicating the early stage of gestation from normal and preeclamptic pregnancies, a time in development that has – until now – has been mostly inaccessible to researchers. In aim 1, we will optimize trophoblast organoid protocols in our laboratory using hiPSCs derived trophoblast differentiation method from donor fibroblasts and will confirm that these organoids phenotypically and functionally behave like first trimester villous tissue. We will then test the hypothesis that the functional capacity of trophoblast organoids derived from hiPSCs obtained from early-onset preeclampsia will be impaired when compared to trophoblast organoids derived from non-hypertensive controls. In aim 2, we will model maternal syndrome of preeclampsia in nude mice with factors made by human placenta. To model human preeclampsia, we will generate trophoblast organoids using hiPSCs derived from placental fibroblasts from women carrying a fetus with trisomy 13, a disorder characterized by 10-fold excess risk of preeclampsia due to extra copy of sFLT1 gene on chromosome 13. We will then test in vivo efficacy of monoclonal antibodies that target the unique C-terminus of human sFLT1-i14 (the isoform that is primate-specific) for enhanced clearance of sFLT1 from systemic circulation. Due to the organoid's ready access and ability to replicate the early stages of development from well- characterized cells, the trophoblast organoid model promises to significantly improve our understanding of preeclampsia and provides rapid screening methods for testing potential drugs and furthering precision medicine methods in obstetrics. Our studies will have major implications not only for the pathogenesis of preeclampsia, but also for short and long-term cardiovascular complication in these women.