The use of pluripotent stem cells as a model for early human placentation
Abstract
[ACCESS RESTRICTED TO THE UNIVERSITY OF MISSOURI AT AUTHOR'S REQUEST.] Throughout gestation, the placenta plays a critical role in ensuring proper development of the fetus. The placenta functions to exchange nutrients, oxygen, and fetal waste, produce and secrete hormones to influence maternal physiology, establish immune protection, and act as a protective barrier. Due to the placenta's many vital functions, any disruption could prompt additional stress on the pregnancy and, therefore, has the potential to disrupt fetal development. Furthermore, the placenta must alter its functions throughout gestation to adapt to the demands of the growing fetus. The earliest placental structure to form is known as the primitive syncytium, which is a highly invasive layer of trophoblast (TB) cells that implant into the maternal uterine wall. Unfortunately, very little is known about this early structure, due to the fact that at this time the mother would be unaware of the pregnancy and sample collection is not practicable on both technical and ethical grounds. It is now well established that human embryonic stem cells (ESC) and induced pluripotent stem cells (iPSC) can be driven along the TB lineage by exposing them to bone morphogenetic protein 4 (BMP4) and inhibiting the signaling pathways that maintain the pluripotent phenotype (FGF2 and ACTIVIN A). The central theme of my dissertation has been to use these stem cellderived TB to model the early placental structure known as the primitive syncytium. My research investigated the use of this stem cell-derived TB model to 1) illustrate phenotypic and genotypic properties of TB cells differentiated from reprogrammed umbilical cord fibroblast cells collected from uncomplicated pregnancies (CTL) with those from infants whose mothers had experienced early onset preeclampsia (EOPE), 2) assess the vulnerability of stem cell-derived TB cells to Zika virus infections and 3) characterize the strain specific effects induced by the African and Asian lineages of Zika virus on TB cells. Our results have shown that 1) TB generated from EOPE pregnancies display enhanced susceptibility to oxidative stress which appears to limit their invasive capacity; 2) stem cell-derived TB are highly susceptible to Zika virus infection and virus induced cell lysis, while the progenitor cells (stem cells) are relatively resistant to Zika induced lysis; and 3) the African lineages, but not the Asian lineages, of the Zika virus induce rapid and severe cell lysis in TB cells (stem cell-derived TB and JAr cells). Taken together, my research demonstrates that stem cell-derived TB provide a unique model system to study placental pathologies as they may occur early in pregnancy.
Degree
Ph. D.
Thesis Department
Rights
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