Doctor of Philosophy
Anatomy and Cell Biology
Renaud, Stephen J.
Proper development of the placenta is vital for pregnancy success. The placenta regulates exchange of nutrients and gases between maternal and fetal blood and produces factors necessary to sustain pregnancy. Thus, maldevelopment of the placenta is linked with serious obstetrical complications that can jeopardize the health of both mother and child. Additionally, the placenta develops in parallel with multiple embryonic organs, notably the heart. Improper placental development can leave the heart vulnerable to environmental insults and result in cardiovascular disease. Therefore, understanding how the placenta forms is of major health importance. The parenchymal cells of the placenta are called trophoblasts, which arise from trophoblast stem (TS) cells differentiating through one of two distinct lineage pathways: syncytiotrophoblast (ST), which regulates maternal-fetal nutrient transfer, and extravillous trophoblasts (EVTs), which remodel the uterine vasculature. However, the molecular mechanisms governing differentiation of TS cells are poorly understood. In this thesis, I show that glial cells missing-1 (GCM1) and OVO-Like 2 (OVOL2) are two transcription factors critical for morphogenesis of the human and mouse placenta, respectively. GCM1 regulates differentiation of human TS cells into both ST and EVTs. Particularly, GCM1 coordinates development and function of EVTs by regulating expression of the EVT regulator ASCL2 and the WNT antagonist NOTUM. In mice, OVOL2 is highly expressed within trophoblasts and loss of OVOL2 results in poor differentiation capacity and abrogated development of the placenta. OVOL2 mediates its effects on mouse placental morphogenesis, in-part, by regulating expression of the stem-associated factor Id2. Interestingly, Ovol2- deficient embryos die prematurely at embryonic day 10.5 due to major defects in heart formation, albeit Ovol2 expression is undetectable in the fetal heart. Poor development of the fetal heart is likely attributed to the absence of a placenta-specific microRNA, mmu-miR- 1249-3p, in extracellular vesicles isolated from Ovol2-deficient TS cells. I further show that placental-derived extracellular vesicles traffic to the embryo in vivo, where they may contribute to nascent heart formation. Collectively, my thesis provides insight into the mechanisms regulating TS cell biology and how the placenta and heart develop in concert to ensure proper development of the embryo.
Summary for Lay Audience
A major goal of my thesis was to identify new proteins important for placental function and development. The placenta is a unique but temporary organ that is the lifeline for a baby while in the womb. It produces hormones that are essential for growth and development of the baby, and serves as the primary respiratory and nutritive organ for the baby. Therefore, maldevelopment of the placenta can negatively affect the health of the baby. Additionally, placental compromise is linked with poor heart formation. In cases of perturbed placental function, the heart is vulnerable, and children are more likely to develop congenital heart disease, a group of serious birth defects that affect 1% of all newborns. Thus, understanding how the placenta forms to support pregnancy is of vital importance. The placenta is comprised of cells called trophoblasts. There are many different kinds of trophoblasts, each with unique functions. These different kinds of trophoblasts are derived from trophoblast stem cells; but how these stem cells form the specialized trophoblasts that make up the placenta is not well understood. In my thesis, I identified novel regulators that are important for trophoblast stem cells to form specialized trophoblast subtypes. My work shows that two factors, glial cells missing-1 and OVO-Like 2, regulate the development of the placenta in humans and mice, respectively. Furthermore, I show that the placenta releases small particles that promote development of the heart. Overall, the work presented in my thesis provides insight into the complexities of trophoblast biology, placental development, and placenta-embryo communication.
Jeyarajah, Mariyan J., "Identifying Novel Transcriptional Regulators in Trophoblast Development" (2023). Electronic Thesis and Dissertation Repository. 9105.
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Available for download on Friday, January 31, 2025