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.
While many diseases of poor placentation, including early pregnancy loss, intrauterine growth retardation and preeclampsia, have their origins in abnormal early placental development, such development cannot be studied in vivo in humans. We will develop stem cell-based models that will, for the first time, provide insight into this part of pregnancy. These models should help to define the pathogenesis of these and related diseases and direct development of novel diagnostic and treatment strategies.
|Roberts, R Michael; Ezashi, Toshihiko; Sheridan, Megan A et al. (2018) Specification of trophoblast from embryonic stem cells exposed to BMP4. Biol Reprod 99:212-224|
|Ezashi, Toshihiko; Imakawa, Kazuhiko (2017) Transcriptional control of IFNT expression. Reproduction 154:F21-F31|
|Jain, Ashish; Ezashi, Toshihiko; Roberts, R Michael et al. (2017) Deciphering transcriptional regulation in human embryonic stem cells specified towards a trophoblast fate. Sci Rep 7:17257|
|Sheridan, Megan A; Yunusov, Dinar; Balaraman, Velmurugan et al. (2017) Vulnerability of primitive human placental trophoblast to Zika virus. Proc Natl Acad Sci U S A 114:E1587-E1596|
|Yunusov, Dinar; Anderson, Leticia; DaSilva, Lucas Ferreira et al. (2016) HIPSTR and thousands of lncRNAs are heterogeneously expressed in human embryos, primordial germ cells and stable cell lines. Sci Rep 6:32753|
|Li, Liping; Tu, Jiaoqin; Jiang, Yao et al. (2016) Effects of Lipopolysaccharide on Human First Trimester Villous Cytotrophoblast Cell Function In Vitro. Biol Reprod 94:33|
|Yabe, Shinichiro; Alexenko, Andrei P; Amita, Mitsuyoshi et al. (2016) Comparison of syncytiotrophoblast generated from human embryonic stem cells and from term placentas. Proc Natl Acad Sci U S A 113:E2598-607|
|Yang, Ying; Adachi, Katsuyuki; Sheridan, Megan A et al. (2015) Heightened potency of human pluripotent stem cell lines created by transient BMP4 exposure. Proc Natl Acad Sci U S A 112:E2337-46|
|Li, Liping; Schust, Danny J (2015) Isolation, purification and in vitro differentiation of cytotrophoblast cells from human term placenta. Reprod Biol Endocrinol 13:71|
|Lee, Kiho; Kwon, Deug-Nam; Ezashi, Toshihiko et al. (2014) Engraftment of human iPS cells and allogeneic porcine cells into pigs with inactivated RAG2 and accompanying severe combined immunodeficiency. Proc Natl Acad Sci U S A 111:7260-5|
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