Neural cell fate in the context of improving translational medicine




Grow, Douglas A.

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Parkinson's disease (PD) is currently an incurable disease in which populations of neurons progressively die as a result of unknown causes. Stem cells can provide a virtually limitless supply of neurons to replace those lost in PD, but all clinical attempts to apply stem cell therapies to humans have failed, despite an abundance of success in rodent studies. The first chapter of this dissertation provides a review of the pathology of PD and the challenges that hinder cell-based therapies as a treatment for PD. We propose the use of nonhuman primates as a preclinical model to address these specific challenges, and we therefore discuss the anatomical and immunological advantages of nonhuman primates pertinent to the study of cell transplantation in Chapter 1. In addition to the lack of an adequate transplantation model, stem cell therapy also suffers from the fact that the efficiency and specificity of current stem cell differentiation protocols remain low. Epigenetic mechanisms have profound influence over cellular identity, and provide a method for the cell to resist or follow cues from specific signaling factors common in directed differentiation protocol. The last section of chapter one discusses one such mechanism, the polycomb repressive complex (PRC) as it is involved in the regulation of the development of a fully mature neuron from the undifferentiated state. The aim of chapter two is to establish the baboon as a preclinical model for testing the efficacy and safety of stem-cell transplantation for PD. Thus, it describes differentiation of baboon fibroblast-derived induced pluripotent stem cells (biPSCs) into neurons. We confirmed that biPSC-derived neurons expressed markers that are upregulated in dopamine neurons in vivo, such as TH, GIRK2, FOXA2, and LMX1A. Using RT-qPCR, we also show that biPSC-derived neurons express NURR1, PAX6, PITX3, FOXA2, LMX1A, TH, and VMAT2. Finally, we used perforated patch-clamp electrophysiology to show our neurons fired spontaneous rhythmic action potentials and stimulation-induced high-frequency action potentials. Epigenetic mechanisms can have great impact on cell fate decisions. A thorough understanding of epigenetic mechanisms in stem cells may be useful in the development of highly specified neuronal differentiation protocols. We therefore decided to interrogate the role one such mechanism may play in regulating production of mature neurons from the immature state. Polycomb-mediated repression by histone 3 lysine 27 trimethylation (H3K27me3) is catalyzed by the PRC1 component EZH2 and is critical for the proper development of the nervous system. In chapter three, we show that H3K27me3 is enriched in both mature and immature neural cells of the dentate gyrus. We also found that H3K27me3 enrichment in the dentate gyrus could be reduced with a novel protein-based Cre-LoxP recombination method.


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induced pluripotent stem cells, Neural Stem Cells, nonhuman primates, Parkinson's disease



Integrative Biology