Pluripotent Stem Cells: Modeling syncytiotrophoblast development and pathogenesis

Summary

Principal Investigator: Danny J Schust
Abstract: DESCRIPTION (provided by applicant): A placenta allows eutherian mammals to give birth to progeny that are already developmentally advanced. A wide range of placental phenotypes exist across taxa to ensure adequate nutrient transfer from mother to offspring. The human placenta forms particularly intimate associations with maternal tissues through two types of cells: 1) syncytiotrophoblast (STB) cells, the fetally-derived trophoblast (TB) cell subset that coats the surface of the villous placenta, and 2) extravillous TB (EVCTB), which invade deeply, interact with maternal decidual immune cells, and remodel the spiral arteries. Both TB subsets are in direct contact with maternal blood and maternal immune cells and both are derived from an ill-defined, stem-cell like, cytotrophoblast (cytoTB) cell subpopulation. Although many adverse pregnancy outcomes may result from poor placental development, the study of the earliest stages of placental development cannot be performed in humans for ethical reasons. For example, alterations in STB development and turnover have been implicated in placental disease, including preeclampsia (PE), the leading single cause of premature birth. STB is the source of "placental debris", cytokines, and pro-inflammatory and anti-angiogenic proteins, which become elevated in mothers diagnosed with PE. Appropriate in vitro models of early placental development are essential if we are to better understand and treat diseases of poor placentation. The first goal of this proposal is to generate STB and its mononucleated precursors from human embryonic stem cells (hESC) that have been treated with BMP4 (BMP-hESC) and inhibitors of activin and FGF2 signaling. We will use this system as a model to study STB emergence, especially the process of cell fusion and cell death, as well as intrinsic and extrinsic factors that influence these transitions. This project has high significance because STB forms the major interface with maternal blood perfusing the placenta and is responsible for the production of endocrine factors such as hCG and exchange of gases, nutrients and waste products The second goal is to demonstrate the utility of the BMP-hESC model to examine the molecular events controlling STB formation and lifespan, with an emphasis on the roles of transcription factors, such as GCM1 &GATA2, fusogenic proteins such syncytin-1 &-2 (ERVW1, ERVFRD-1, respectively) and a presently little understood HERV envelope gene product (ERV-Fb1) that inhibits cell-cell fusion. A third goal is to assess whether some features of PE can be unearthed in the BMP-hESC model. Our hypothesis is that TB from a sub-group of conceptuses whose mothers develop PE early in their pregnancies is unusually sensitive to high oxygen tensions. Since STB will only begin to encounter well-oxygenated maternal blood after the uteroplacental arteries "open" towards the end of the first trimester of pregnancy, the oxygen hypersensitivity of cells derived from PE placentas may cause them to turnover at an accelerated rate and shed cell contents and debris into the circulating maternal blood more quickly than normal STB. We will test this hypothesis in vitro using iPSCs derived from the umbilical cords of babies born to mothers with severe preeclampsia and gestational age-matched control iPSCs.
Funding Period: 2013-08-15 - 2018-04-30
more information: NIH RePORT

Top Publications

  1. ncbi Differentiation of trophoblast cells from human embryonic stem cells: to be or not to be?
    R Michael Roberts
    Division of Animal Sciences
    Reproduction 147:D1-12. 2014

Detail Information

Publications1

  1. ncbi Differentiation of trophoblast cells from human embryonic stem cells: to be or not to be?
    R Michael Roberts
    Division of Animal Sciences
    Reproduction 147:D1-12. 2014
    ..By analogy to other differentiation systems, our debate is broadly applicable, as it articulates higher and more challenging standards for judging whether a given cell type has been genuinely produced from hPSC differentiation. ..

Research Grants30

  1. Semi-volatile PCBs: Sources, Exposures, Toxicities
    Larry W Robertson; Fiscal Year: 2013
    ..These data and dietary studies in the last Aim will provide a scientific basis for risk assessment and advice for stakeholders with the ultimate goal to protect highly-exposed individuals and populations. ..
  2. Center for the Study of Reproductive Biology and Women's Health
    Jeffrey W Pollard; Fiscal Year: 2013
    ..He holds several senior administrative appointments in the College of Medicine and is well able to administer the proposed SCCPIR internally and to enable effective interactions with other SCCPIRs. ..
  3. Lifecourse Exposures &Diet: Epigenetics, Maturation &Metabolic Syndrome
    KAREN EILEEN PETERSON; Fiscal Year: 2013
    ..Career development and training activities will draw upon extensive institutional resources and will be fully integrated with the Center's Research Projects and Cores. ..
  4. Stanford University Center for Reproductive and Stem Cell biology
    Margaret T Fuller; Fiscal Year: 2013
    ..abstract_text> ..
  5. Modeling human trophoblast stem cells using iPS cells derived from molar placenta
    Mana M Parast; Fiscal Year: 2013
    ....
  6. Pluripotent human stem cells as models for normal and diseased trophoblast
    ROBERT MICHAEL ROBERTS; Fiscal Year: 2013
    ..Also by generating such pluripotent cells from umbilical cords of babies born to mothers that developed pre-eclampsia, we hope to recreate the cell type that caused the disease in the first place. ..
  7. Translational Analyses of Chronic Aberrant Behavior Across the Life Span
    ISER DELEON; Fiscal Year: 2013
    ..Evidence arising from this multi-site, multi-faceted approach to the treatment of CAB in IDD will make it possible to design better therapeutic individuals with IDD to lead better lives. ..
  8. Pathogenesis of Novel Forms of Osteogenesis Imperfecta
    BRENDAN HL LEE; Fiscal Year: 2013
    ..The human genetic studies will supported by the Genomics Core led by Dr. D. Cohn. The implementation and integration of the work will be supported by Dr. B. Lee in the Administrative Core. ..
  9. Integrating Environmental Cues at the Maternal-Fetal Vascular Interface
    Emin Maltepe; Fiscal Year: 2013
    ..Importantly, the combination of directed and unbiased approaches designed to dissect the pathways involved may lead to novel pharmacological targets to prevent or treat this intractable disorder. ..
  10. CARDIOVASCULAR DYNAMICS AND THEIR CONTROL
    John E Hall; Fiscal Year: 2013
    ..End of Abstract) ..
  11. Program Project: GENE MUTATION AND RESCUE IN HUMAN DIAPHRAGMATIC HERNIA
    Patricia K Donahoe; Fiscal Year: 2013
    ..Further, the methods devised for this study of CDH may have broader implications across other congenital anomalies. ..
  12. ACE2 Deficiency: A new model of maternal and fetal growth restriction.
    Liliya M Yamaleyeva; Fiscal Year: 2013
    ..Specific Aim 3 will determine whether maternal or fetal ACE2 KO is necessary for the fetal weight restriction using embryo transfer. ..
  13. Pregnancy specific glycoprotein 1 activates transforming growth factor beta
    Gabriela S Dveksler; Fiscal Year: 2013
    ..This project will define the mechanism of action o PSG1 and address a possible novel mechanism of TGF-b1 and TGF-b2 activation. ..
  14. A Novel Model for Assessing the Effects of BPA Exposures on Human Placentation
    Susan J Fisher; Fiscal Year: 2013
    ..These findings will enable future experiments to determine the in vivo relevance of these alterations by studying placental samples collected from women whose blood levels of BPA have been measured. ..
  15. Diverse Roles of Reactive Oxygen Species and Inflammation in Vascular Disease
    Kathy K Griendling; Fiscal Year: 2013
    ..Ultimately, this research may establish new unifying concepts linking conditions that alter vascular oxidant stress and inflammation to the molecular processes underlying vasculopathies. (End of Abstract) ..
  16. HCMV inhibition of cytotrophoblast differentiation through dysregulation of Wnt/?
    Deborah E Sullivan; Fiscal Year: 2013
    ....
  17. EPIDEMIOLOGY OF ALCOHOL PROBLEMS
    Thomas K Greenfield; Fiscal Year: 2013
    ..We plan to build research capacity in the Center and other organizations, enhance careers of new investigators, and make key findings accessible to researchers, policy makers, practitioners, and the public. ..
  18. Angiogenic factors, abnormal placentation and adverse pregnancy outcomes
    Sarosh Rana; Fiscal Year: 2013
    ..The combined expertise of mentors and collaborators provide a unique opportunity for the applicant to achieve the goals of this project and to start a career as an independent investigator. ..
  19. HIF-1 Alpha Regulation of Trophoblast Differentiation in Vivo
    Thomas L Brown; Fiscal Year: 2013
    ..Understanding how oxygen sensing regulators control normal placental development will help us understand how pregnancy-associated disorders arise, can be detected, and treated. ..
  20. Center for Reproductive Science and Medicine
    Pamela L Mellon; Fiscal Year: 2013
    ..The SCCPIR Human Ovary Tissue Bank provides tissue to NIH-funded investigators nation-wide. ..
  21. Sirt1-PPARgamma signaling in placental development and fetal growth disorders
    Mana M Parast; Fiscal Year: 2013
    ..This project has the potential to identify therapeutic targets for these diseases, leading to a decrease in perinatal morbidity and mortality. ..
  22. Pathophysiology of Alveolar Epithelial Lung Injury
    Jacob I Sznajder; Fiscal Year: 2013
    ..The insights gained from the data generated from these studies will provide novel molecular targets for the development of new therapeutic strategies to treat patients with lung injury. ..
  23. Function and Integration of Stem Cell-derived Cardiac Tissue Patch
    Nenad Bursac; Fiscal Year: 2013
    ..The knowledge obtained in this project will allow us to pursue in the future engineering of a functional cardiac tissue patch made of human stem cells for potential clinical applications. ..
  24. Function of Toll-Like Receptors Throughout Gestation
    GIL G MOR; Fiscal Year: 2013
    ....
  25. GATA Factor Function in Trophoblast
    Soumen Paul; Fiscal Year: 2013
    ..We will also determine whether GATA3 have differentiation stage specific target genes. ..
  26. Human Capital Interventions Across Childhood and Adolescence
    GREG JOHN DUNCAN; Fiscal Year: 2013
    ..Taken together, the group's involvement with multiple projects as well as seminars, jointly-authored papers and other core activities will constitute a research network - the Irvine Network on Interventions in Development. ..
  27. Placental injury and microRNA
    Yoel Sadovsky; Fiscal Year: 2013
    ....