Placenta is a transient organ that connects mom and baby during pregnancy, and supplies nutrients and oxygen for intrauterine fetal growth. It has been known that abnormal placentation can lead to preeclampsia (PE), a major complication affecting 2-8% of all pregnancies, presenting as new onset hypertension and proteinuria in the latter half of pregnancy. PE is associated with growth restriction and preterm delivery of the baby, both of which are associated with adverse outcomes, in both the perinatal period and later in life. Many studies point to abnormal differentiation of placental epithelial cells, called trophoblast, as the etiology of PE. Specifically, development of invasive extravillous trophoblast (EVT) and/or their function are affected in PE, leading to shallow implantation and placental insufficiency. However, while these are some accepted hypotheses about the nature of the disease, the underlying pathophysiology is still not fully understood mainly due to the lack of a truly representative model system. Over the past decade, the development of methods to generate induced pluripotent stem cells (iPSC) has led to the ability to model numerous human diseases, including those originating in the cardiovascular and nervous systems and the pancreas. In addition, over the same time period, multiple groups, including ours, have shown that iPSCs can be differentiated into trophoblast, using the growth factor, bone morphogenetic protein 4 (BMP4). My own work has in fact provided proof-of-concept that defects in trophoblast differentiation, specifically those associated with Trisomy 21, can be modeled using iPSCs. I therefore plan to apply this technology to model placental dysfunction in PE, with the following three aims: 1) I will establish iPSCs by reprogramming umbilical cord mesenchymal stem cells (UC-MSCs) from six PE and six gestational age-matched control (non-PE) placentas, using non-integrative Sendai virus-based method. I will assay their pluripotency, and characterize their epigenetic memory before and after reprogramming, evaluating both DNA methylation and histone H3 modifications. 2) I will characterize the trophoblast derived from both PE and control iPSCs, evaluating their ability to differentiate into both invasive EVT and multinucleated syncytiotrophoblast (STB). I will also evaluate both the gene expression and epigenetic profile of trophoblast derived from PE and non-PE iPSC. 3) Finally, I will test the effect of environmental factors, known to be involved in the pathogenesis of PE, on trophoblast derived from PE and non-PE iPSCs, including the effects of hypoxia, pro-inflammatory cytokines, and specific subpopulations of decidual leukocytes. The successful completion of this project will provide us with new models for studying this devastating disease, and thus the ability to generate novel diagnostic tools and therapeutic modalities in order to improve care for these women and babies.
Preeclampsia is a pregnancy complication with a high rate of maternal and neonatal morbidity and mortality. However, currently the only management option is delivery, which often leads to the preterm birth and associated complications. This proposal aims to establish stem cell-based models of this disease, which can be used to study the underlying pathophysiology, develop diagnostic tools, and identify therapeutic targets.
