Differential Effects of PDGFA and PDGFC Ligands on Neural Stem and Progenitor Cells
Date
2023-12-15
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Abstract
My thesis describes the behaviour of subventricular zone (SVZ)-derived neural stem and progenitor cells (here called NPCs) from young adult mice during exposure to members of the platelet-derived growth factor (PDGF) family of ligands. Two novel findings arise from my work. First, P53 null NPCs cultured in PDGFA transform in vitro acquiring a phenotype and genotype that closing resembles that of human glioblastoma (GBM). Second, NPCs cultured in PDGFC form small quiescent spheres of pluripotential neural stem cells (NSCs) that can be maintained in a stem-like state in PDGFC or induced to proliferate or differentiate by modifying the growth factor environment. My work is of interest to cancer biologists studying the origins of GBM and oncologists seeking ways to prevent this cancer or intercept it at an early more treatable stage. My thesis is also of interest to stem cell biologists and neurobiologists seeking new models to study the stem cell niche in the mammalian brain and brain maturation in health and disease. I have uncovered the mechanism of transformation of P53 null NPCs in PDGFA by analyzing an in vitro model of oncogenesis in which the earliest events can be detected, and their consequences tracked over time. I discovered that defective mitosis initiates a series of events that culminate in a GBM-like cancer. I also discovered that cells isolated from the SVZ using PDGFC have the behavioral and biomarker profile that would be expected of true stem cells. My findings stand in contrast to the gold standard method for isolating and studying NSCs in which cells from the SVZ are cultured in epidermal growth factor plus fibroblast growth factor (EGF/FGF) and where they divide rapidly and continuously. I also found that PDGFC could replace PDGFA in the isolation and propagation of oligodendrocyte progenitor cells (OPCs), a cell type of increasing interest. Overall, my work adds to our understanding of the biology of two important members of the PDGF family of ligands and describes new model systems that can be exploited further.
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Keywords
Neural stem cells, PDGFA, PDGFC
Citation
Omairi, H. (2023). Differential effects of PDGFA and PDGFC ligands on neural stem and progenitor cells (Doctoral thesis, University of Calgary, Calgary, Canada). Retrieved from https://prism.ucalgary.ca.