California's Stem Cell Agency

Preeclampsia (PE) is a pregnancy complication, characterized by high blood pressure and abnormal kidney function, which affects 5-8% of all pregnancies. It is responsible for a significant proportion of maternal deaths and growth-restricted babies; it is also a major reason why obstetricians induce delivery prematurely, resulting in additional neonatal complications, often requiring extended stays in neonatal intensive care units. PE is a disease of the placenta, an organ which supports the fetus during intrauterine life. In PE, a subpopulation of placental cells called “extravillous trophoblast” (EVT) fail to properly develop: in their absence, the placenta does not receive enough blood supply and therefore cannot support fetal growth. PE is difficult to study: it spontaneously develops only in higher primates, and available human trophoblast cell lines are of limited use. During the past year, we have focused on screening for drugs which can increase EVT differentiation of normal human ES-derived trophoblast precursors. We have identified several compounds so far, and are currently performing additional experiments to find the optimal dosage at which these drugs can induce EVT formation. We have also started to develop “disease-in-a-dish” models for PE, by collecting cells from placentas of several patients who developed PE during their pregnancy. We plan to generate “induced pluripotent stem cells” (iPSCs) from these placental cells, which can then be evaluated for their ability to make trophoblast cells, including EVT. We suspect that some of these PE-iPSCs will have defects, either in formation of EVT or in their ability to function as EVT. We will then test the ability of the drugs, identified above, to restore EVT differentiation in these PE cell culture models.

Preeclampsia (PE) is a pregnancy complication, characterized by high blood pressure and abnormal kidney function, which affects 5-8% of all pregnancies. It is responsible for a significant proportion of maternal deaths and growth-restricted babies; it is also a major reason why obstetricians induce delivery prematurely, resulting in additional neonatal complications, often requiring extended stays in neonatal intensive care units. PE is a disease of the placenta, an organ which supports the fetus during intrauterine life. In PE, a subpopulation of placental cells called “extravillous trophoblast” (EVT) fail to properly develop: in their absence, the placenta does not receive enough blood supply and therefore cannot support fetal growth. PE is difficult to study: it spontaneously develops only in higher primates, and available human trophoblast cell lines are of limited use. During the past year, we have completed validation of results from our screening for drugs which can increase EVT differentiation of normal human ES-derived trophoblast precursors. We have identified a specific combination of three drugs which optimally induce EVT formation. We are also in process of developing “disease-in-a-dish” models for PE, by reprogramming cells collected from placentas of patients who had either a normal pregnancy or a pregnancy complicated by PE. We then plan to evaluate these “induced pluripotent stem cells” for their ability to make trophoblast cells, including EVT. We suspect that some of these PE-iPSCs will have defects, either in formation of EVT or in their ability to function as EVT, including hormone secretion and invasion. We will then test the ability of the optimized 3-drug-combination, identified above, to restore EVT differentiation and/or function in these PE cell culture models.