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Thesis Format

Integrated Article

Degree

Doctor of Philosophy

Program

Anatomy and Cell Biology

Supervisor

Stephen J Renaud

Abstract

Development of the placenta and embryo is a highly orchestrated process that is vulnerable to changes in the in utero environment. Maternal immune activation (MIA) during pregnancy is a major risk factor for many obstetric complications and predisposes offspring to growth restriction as well as cognitive and neurobehavioral deficits; however, the mechanisms underlying these risks remain unknown. In this thesis, I aimed to determine the effect of MIA on development of the placenta and fetal brain. By administering the viral mimetic polyinosinic:polycytidylic acid to pregnant rats as a model of MIA, I demonstrated that a maternal antiviral response is associated with impaired placental and fetal growth and altered fetal brain structure. Specifically, I showed that intraperitoneal injection of polyinosinic:polycytidylic acid into pregnant rats results in MIA, decreased placental and fetal size, and reduced expression of several paternally-expressed imprinted genes. Moreover, I determined that type I interferons impair differentiation of rat trophoblast stem cells. Secondly, by analyzing the cerebral cortex of midgestation rat fetuses one week following maternal injection of polyinosinic:polycytidylic acid or saline, I found that fetuses exposed to MIA had increased neural precursor cell self-renewal. This finding was recapitulated using neurospheres generated from these fetal brains and was associated with altered expression of Notch signaling components. Lastly, I found that uterine natural killer cells, the most prevalent immune cells in rat decidua in early pregnancy, produce the multifunctional protein osteopontin, which may contribute to decidual and placental development. Collectively, this work provides insight into the role of MIA and decidual immune cells in modulating development of the placenta and fetal brain.

Summary for Lay Audience

The placenta is a necessity of human reproduction. Connecting a mother to her developing baby, the placenta sustains pregnancy by ensuring nutrients and oxygen reach the baby and by acting as a protective barrier. When the placenta does not develop properly, dangerous pregnancy complications can occur which put both mother and baby at risk of developing short and long-term illness or death. Factors that cause high risk of placental maldevelopment include infection and inflammation, and I believe that the mother’s immune cells (which fight infections) play a role in the development of these complications during pregnancy. Using rats, I found that inflammation during early pregnancy altered the way the placenta forms and reduced the size of pups. Moreover, I found that inflammation during rat pregnancy changed the pups’ brain structure, which could help explain why individuals exposed to infection while they are in the womb have an increased chance of problems with brain function. Additionally, I found that a protein called osteopontin is produced by immune cells close to the placenta and may have an important role in how the placenta forms. Collectively, these findings can help us understand how infections and inflammation lead to poor placental development and smaller babies.

Creative Commons License

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

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