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.
Reporting Period:
Year 2
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 validating the results from our screening for drugs which can increase EVT differentiation of normal human ES-derived trophoblast precursors. We have currently focusing on using combinations of various drugs to find the optimal combination for induction of EVT formation.
We have also started to develop “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. Such “induced pluripotent stem cells” (iPSCs) 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.
Reporting Period:
Year 3
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.
Reporting Period:
Year 5/NCE
Through the generous support of this award, we have been able to establish, for the first time, disease-in-a-dish models for the common pregnancy disorder, preeclampsia. This is an extremely difficult disease to study due to its origin during early pregnancy and lack of proper animal models which can recapitulate human placental development. Using our preeclamptic iPSC lines, we have been able to find a common defect in early differentiation of placental cells, a defect which further explains the abnormal development and function of the placenta in this pregnancy complication. We have also been able to identify small molecules which at least partially reverse this phenotype, promoting differentiation of the invasive placental cells which show abnormal development and function in preeclampsia. We are currently beginning to further test these small molecules as potential therapeutics for prevention of this devastating pregnancy disorder, a feat which would not have been conceivable in the not-so-distant past. Given this success, we have also begun to expand this work into modeling other placenta-based pregnancy complications, including spontaneous preterm birth and placenta accreta. Establishment of such models will both shed light on the pathophysiology of these diseases and provide a platform for identification of diagnostic biomarkers and therapeutic targets.
Grant Application Details
Application Title:
Human pluripotent stem cell-based therapeutics for preeclampsia
Public Abstract:
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. Using normal human ES-derived trophoblast precursors, we propose to screen for drugs which can increase EVT differentiation. We will also apply stem cell-based technology to cells from placentas of PE patients, in order to develop “disease-in-a-dish” models for PE. We will then test the ability of the drugs, identified above, to restore EVT differentiation in these PE models. If successful, this application will 1) establish the first true cell culture model for preeclampsia, and 2) identify drugs for its treatment.
Statement of Benefit to California:
On an average day in California, 149 babies are born prematurely. Many of these babies will require weeks of care in a neonatal intensive care unit, at an average per patient cost of $25,000 (compared to the $1,500 per patient cost of a baby born at term). The #1 reason obstetricians induce preterm delivery is a disease called preeclampsia, where mom develops high blood pressure and other serious complications during pregnancy. Preeclampsia is also responsible for ~20% of maternal deaths in pregnancy. Preeclampsia is not well-understood, but is known to be a disease of the placenta, an organ which forms the interface between mother and baby. Our lab is one of few in the world that focuses on stem cells which give rise, not to the baby, but to the placenta: these are called trophoblast stem cells. We have recently developed a human trophoblast stem cell model, which can be used to study events during placental development, never before possible in the human. This proposal, if funded, would extend these findings to develop ground-breaking models for studying preeclampsia and identifying drugs for its treatment. If successful, this research would benefit the state of California by developing therapies which would prevent preeclampsia, and therefore a significant proportion of preterm births and its complications. This would lead, not only to improved health of moms and babies, but also save the state millions in cost of prolonged stays in neonatal intensive care units.
