While there is substantial understanding of the molecular decisions which direct placental development in the mouse, the significance for human placental development remains elusive, in part due to the inability to investigate differentiation at the level of the embryo and the implantation site during human pregnancy. Our preliminary studies suggest that extracellular matrix can play an important instructive role in trophoblast differentiation from hES cells within embryoid bodies. Human ES cells offer an exciting opportunity to address this critical developmental window at the cellular and molecular level. Our central hypothesis is that placental morphogenesis requires the initiation of intrinsic pathways and response to extrinsic influences/cues to coordinate trophoblast differentiation and formation of the chorionic villi. We propose to establish and characterize an embryoid body model for placental development to address this hypothesis.
Specific Aim 1 is to define trophoblast formation and differentiation in hES cells [(lines WA01, WA07 and WA09 in the NIH Human Embryonic Stem Cell Registry, www.escr.nih.gov)] directed to form embryoid bodies and exposed to varied extracellular matrix environments.
Specific Aim 2 is to evaluate ES cell-placental mesenchymal cell co-cultures in vitro and in vivo to model placental morphogenesis. An inability to initiate appropriate early placental function (embryo attachment, invasion, and hormone secretion) is likely to contribute to embryo loss in early pregnancy. Additionally, inappropriate placental development and abnormal establishment of the maternal-fetal interface are thought to contribute to the pathogenesis of diseases of later pregnancy (e.g., preeclampsia, fetal growth restriction). The unique structural organization of the primate placenta among mammals makes it difficult to extrapolate results from non-primate species. This proposal will allow us to develop the tools to advance a novel system for the study of primate placental biology. ? ?

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21HD046919-01A2
Application #
6966524
Study Section
Cellular, Molecular and Integrative Reproduction Study Section (CMIR)
Program Officer
Tasca, Richard J
Project Start
2005-07-05
Project End
2007-06-30
Budget Start
2005-07-05
Budget End
2006-06-30
Support Year
1
Fiscal Year
2005
Total Cost
$140,066
Indirect Cost
Name
University of Wisconsin Madison
Department
Veterinary Sciences
Type
Other Domestic Higher Education
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715
Golos, T G; Giakoumopoulos, M; Gerami-Naini, B (2013) Review: Trophoblast differentiation from human embryonic stem cells. Placenta 34 Suppl:S56-61
Golos, Thaddeus G; Giakoumopoulos, M; Garthwaite, M A (2010) Embryonic stem cells as models of trophoblast differentiation: progress, opportunities, and limitations. Reproduction 140:3-9
Giakoumopoulos, Maria; Siegfried, Leah M; Dambaeva, Svetlana V et al. (2010) Placental-derived mesenchyme influences chorionic gonadotropin and progesterone secretion of human embryonic stem cell-derived trophoblasts. Reprod Sci 17:798-808
Douglas, Gordon C; VandeVoort, Catherine A; Kumar, Priyadarsini et al. (2009) Trophoblast stem cells: models for investigating trophectoderm differentiation and placental development. Endocr Rev 30:228-40
Golos, Thaddeus G; Pollastrini, Leah M; Gerami-Naini, Behzad (2006) Human embryonic stem cells as a model for trophoblast differentiation. Semin Reprod Med 24:314-21
Liu, Yi-Ping; Dambaeva, Svetlana V; Dovzhenko, Oksana V et al. (2005) Stable plasmid-based siRNA silencing of gene expression in human embryonic stem cells. Stem Cells Dev 14:487-92