The human placenta facilitates many key functions during pregnancy, including uterine invasion, vascular remodeling, hormone secretion, immune regulation, and maternal-fetal exchange. Placental research, however, has been limited in part by the unrepresentative nature of traditional models. The objective of this doctoral thesis was to build and characterize novel, in vitro models that reintegrated important anatomical and environmental elements of the human placenta, thus enabling more physiologically-accurate assessments of placental function. In our first model, we manipulated the thickness of the extracellular matrix surface to promote the self-assembly of trophoblast cells into three-dimensional (3D) aggregates that exhibited increased genetic and functional markers of syncytial fusion. In our second model, we established a high-throughput platform to generate 3D trophoblast spheroids that underwent dynamic invasion and migration, expressed transcriptomic profiles redolent of the extravillous trophoblast phenotype, and responded to various drugs relevant to pregnancy. In our third model, we developed a trophoblast-endothelial co-culture model of the placental barrier that underwent syncytial fusion, exhibited size-specific barrier permeability, and functioned under physiologically-relevant oxygen tensions. In conclusion, our models may each serve as valuable tools for researchers, contribute to investigations of different aspects of placental biology, and aid in the screening of drugs and toxins for pregnancy. / Thesis / Doctor of Philosophy (PhD) / The human placenta is an important organ that helps regulate the health of both the mother and fetus during pregnancy. Researchers have traditionally studied the placenta through the use of animals or isolated cells, but these have been criticized for not being similar enough to the human placenta. Our objective was to build models that better resembled the structure and environment experienced by the human placenta within the body, such that we could better study its function. During the course of my doctoral work, I built and analyzed three models of the human placenta using human cells that were grown in three dimensions, in multiple layers, and/or in a specific environment. Our first model demonstrated that placental cell behaviour and function can be controlled by altering the thickness of the surface we grew them on. Our second model grew placental cells in three-dimensions and mimicked the invasion process into the mother’s uterus during early pregnancy. Our third model grew placental cells with blood vessel cells to form the barrier that regulates the passage of all substances between the mother and fetus during pregnancy. We also tested the impact of low oxygen on the placental barrier’s formation and function. Overall, we discovered that placental cells could indeed function more similarly to how we expect them to in the body when we design platforms that better resemble their structure and environment. Our model development work provides new information about placental biology and may serve as valuable tools in research and drug development.
| Identifer | oai:union.ndltd.org:mcmaster.ca/oai:macsphere.mcmaster.ca:11375/25323 |
| Date | January 2020 |
| Creators | Wong, Michael K. |
| Contributors | Raha, Sandeep, Medical Sciences |
| Source Sets | McMaster University |
| Language | English |
| Detected Language | English |
| Type | Thesis |
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