Electronic Thesis and Dissertation Repository

Thesis Format

Integrated Article

Degree

Doctor of Philosophy

Program

Anatomy and Cell Biology

Supervisor

Lala, Peeyush. K

2nd Supervisor

Renaud, Stephen J.

Co-Supervisor

Abstract

The human placenta is an invasive tumor-like structure, this invasion being physiological. A subset of placental trophoblast called extra-villous trophoblast invades the uterine decidua and remodels uterine arteries into low-resistance, high-flow tubes to permit adequate flow of maternal blood to nourish the fetus. A poor extra-villous trophoblast invasion and uterine arterial remodeling can lead to fetal growth restriction and a serious pregnancy-associated maternal disease preeclampsia. Decorin, a leucine-rich proteoglycan produced by uterine decidual cells restrains multiple trophoblast functions: self-renewal and differentiation of trophoblast stem cells, migration, invasion, proliferation and endovascular differentiation. Additionally, decidual overproduction of decorin was associated with preeclampsia, and increased decorin levels in the maternal plasma during the second trimester could predict preeclampsia.

I discovered that decorin plays a critical role in maturation of human endometrial stromal cells into decidual cells. Using CRISPR-Cas9 approach for knocking out decorin, I showed that decorin-depleted human endometrial stromal cells failed to mature, as revealed by fibroblastic morphology and reduced production of decidual cell maturation markers, insulin like growth factor protein-1 and prolactin. I also found that interleukin 1 beta produced by trophoblast, macrophages and endometrial glands is the main stimulus for decorin production in the decidua by recruiting a transcription factor, nuclear factor kappa B. Additionally, I discovered a new microRNA-mediated mechanism of decorin action on trophoblast. Two microRNAs (let 7c-5p and 512-3p), induced by decorin restrained multiple trophoblast functions known to be compromised in preeclampsia. They were elevated in preeclampsia-associated placentas. Collectively, my research is fundamental to understanding the pathogenesis of preeclampsia. This knowledge can be exploited to improve maternal and fetal health. For example, decorin induced microRNAs may be used as a biomarker for early diagnosis and intervention of preeclampsia. Furthermore, non-toxic molecules that can reduce decorin production by decidual cells may have therapeutic potential.

Summary for Lay Audience

During pregnancy, the mother’s uterus undergoes a process called decidualization in which uterine cells transform into specialized cells called decidual cells. This process is essential for implantation of the embryo and development of the placenta. The placenta is the physical connection between a mother and her baby and must invade the mother’s uterine blood vessels to draw nutrients for the baby. This placental invasion is exquisitely controlled by many locally-derived molecules to maintain the health of the mother and the developing baby. If this invasion is not adequate, it can result in poor blood flow to the baby, leading to fetal growth restriction and also a serious maternal disease called preeclampsia. Fetal growth restriction has a life-long impact on the baby’s health with an increased risk of developing diabetes and heart disease. Preeclampsia can be life-threatening to the mother, because of high blood pressure, kidney damage and chance of stroke. Delivering the placenta and the baby can only cure it. It is also risky for the baby due to the need for premature delivery. Many uterine molecules control placental invasion to maintain a healthy balance including a small protein, decorin which is made by decidual cells. Decorin controls placental invasion and its over-production is associated with preeclampsia. But its role in decidual cell development is not known. Therefore, I explored this role of decorin and found that decorin production increases during decidualization and is necessary for the decidual cell maturation. Moreover, I found that another protein Interleukin 1beta is the key stimulus for decorin production. Additionally, I found out that decorin action on placental cells could be due to small RNAs called microRNAs, which can be biomarkers for preeclampsia. Collectively, these findings can help us improve our understanding of, early diagnosis and management of preeclampsia.

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