In partial fulfillment of the requirements for the degree of
Doctor of Philosophy in Bioinformatics
in the School of Biological Sciences
Eunbi Park
Defends her thesis:
Modeling emergent patterning within pluripotent colonies through Boolean canalizing functions
Wednesday, April 17th, 2024
11:00 AM
Krone Engineered Biosystems Building (EBB), Room #5029
Zoom Link: https://gatech.zoom.us/j/98921652004?pwd=QmxVZUNxdVgvMVhYU1BUMGs4alJ0dz09
Meeting ID: 989 2165 2004
Thesis Advisor:
Dr. Melissa L. Kemp
Wallace H. Coulter Department of Biomedical Engineering
Georgia Institute of Technology and Emory University
Committee Members:
Dr. Ahmet F. Coskun
Wallace H. Coulter Department of Biomedical Engineering
Georgia Institute of Technology and Emory University
Dr. Elena S. Dimitrova
Mathematics Department
California Polytechnic State University
Dr. Jeffrey T. Streelman
School of Biological Sciences
Georgia Institute of Technology
Dr. Matthew P. Torres
School of Biological Sciences
Georgia Institute of Technology
Dr. Denis V. Tsygankov
Wallace H. Coulter Department of Biomedical Engineering
Georgia Institute of Technology and Emory University
Abstract:
The early events of human induced pluripotent stem cell (hiPSC) differentiation require collective intercellular communication at both local and long distances for symmetry breaking and pattern formation. It is currently unclear which mechanisms take priority in context-specific situations, and resolving these mechanisms is needed to advance hiPSC-derived tissue engineering. Prior work reported intracellular and intercellular regulation of the FGF/ERK/GATA6 pathway in the mouse blastocyst as a driver of differentiation and self-organization. Computational models capable of simulating intrinsic and/or neighbor-to-neighbor mechanisms provide a useful approach to analyze the role of signaling in multicellular organization during the initial loss of pluripotency.
The objective of this research was to investigate the dynamics of emergent patterning and collective intra-/inter-cellular communication that directs early cell fate decisions in hiPSCs. To enable the interpretation of cellular interactions, a novel pipeline was developed to quantify the differences between spatial organization obtained from both in vitro microscopy images and in silico modeling outcomes using topological data analysis (TDA). Next, I performed characterization of FGF/ERK/GATA6 pathway during emergent pattern formation under multiple molecular perturbations, elucidating context-specific attributes in two-dimensional and three-dimensional culture conditions. Finally, a Python agent-based model of hiPSC colony patterning was created with Boolean networks to discriminate between putative mechanisms of cell fate decisions and compared experimentally observed patterns via TDA. Overall, this work demonstrates that the strategies of quantifying spatial organization and modeling and testing engineered hiPSCs in colonies and organoids are tractable alternative approaches to embryonic systems, allowing for the identification of modes of intercellular communication that determine cell fates.