Electronic Thesis and Dissertation Repository

Thesis Format

Monograph

Degree

Master of Science

Program

Anatomy and Cell Biology

Supervisor

Renaud, Stephen J.

Abstract

Preeclampsia is a common and serious complication of pregnancy with no cure except premature delivery. The root cause of preeclampsia is improper development of the placenta, the temporary organ supporting fetal growth. In preeclamptic placentas, a low O2 environment persists due to dysregulated blood flow. My data show that low O2 inhibits differentiation and fusion of progenitor cytotrophoblast cells into a multinucleated syncytiotrophoblast and may thus contribute to the poor placentation in preeclampsia; however, the underlying mechanisms are not well understood. Since low O2 activates a transcription factor complex in cells known as the hypoxia-inducible factor (HIF), I hypothesized that HIF signaling under low O2 impairs placental syncytiotrophoblast formation by altering gene expression. I showed that knockdown of ARNT (a key component of HIF) restores syncytialization under low O2. I also identified downstream targets of HIF that may control this process, which could aid in developing novel therapeutics for preeclampsia.

Summary for Lay Audience

Preeclampsia is a common and serious complication of pregnancy and is a leading cause of sickness and death for pregnant women and babies globally. It presents as sudden-onset high blood pressure and blood vessel damage in mothers that can progress to organ failure, stroke, and death of the mother and/or baby. There is no cure except stopping the pregnancy early and delivering the baby, which can result in both immediate and long-term health problems for the prematurely delivered infant. The root cause of preeclampsia is improper development of the placenta – the temporary organ supporting growth of the baby. Developing safe and effective treatments for the underlying placental dysfunction in preeclampsia is challenging since we do not have a complete understanding of why the placenta forms abnormally in these pregnancies. In preeclamptic placentas, a low O2 environment persists due to dysregulated blood flow. My data show that low O2 inhibits placental stem cell differentiation and may thus contribute to the poor placental development/function characteristic of pregnancies with preeclampsia; however, why this happens is not well understood. I suspected that the hypoxia-inducible factor (HIF), a molecule activated within cells under low O2 to help cells adapt, plays an important role in the inhibition of placental stem cell differentiation and in the development of preeclampsia. The goal of this study was to assess whether HIF signaling under low O2 inhibits placental stem cell differentiation, and if so, to identify genes regulated by HIF that underlie this inhibition and could be targeted to restore differentiation. My results demonstrated that blocking HIF signaling restores the capacity of placental stem cells to differentiate when cultured under low O2, suggesting that HIF contributes to poor stem cell differentiation in low O2 environments. I also identified downstream targets of HIF that may be responsible for inhibiting placental stem cell differentiation under low O2 conditions. Next steps include determining whether altering expression of certain HIF target genes could alleviate impaired differentiation in low O2. This study will open doors to develop and test novel therapeutics that could restore placental stem cell differentiation and improve prevention and management of preeclampsia.

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Creative Commons Attribution 4.0 License
This work is licensed under a Creative Commons Attribution 4.0 License.

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Available for download on Sunday, August 04, 2024

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