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Does epigenetic memory influence the differentiation of MSNs from fetal ganglionic eminence derived iPS cells?

Bartley, Oliver Jay Michael 2019. Does epigenetic memory influence the differentiation of MSNs from fetal ganglionic eminence derived iPS cells? PhD Thesis, Cardiff University.
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Cell replacement therapy for Huntington’s Disease requires a transplantable source of authentic medium spiny neuron (MSN) progenitors from a renewable cell source. Human pluripotent stem cells (hPSC) theoretically fit the required criteria, but without further research it is unlikely we will realise their potential for this purpose, as presently we cannot reliably produce sufficient authentic MSN progenitors with these cells. There is a growing body of work that has demonstrated human induced-PSCs (hiPSC) retain an epigenetic memory of their tissue of origin, which can enhance their differentiation towards cellular phenotypes similar to that tissue of origin. As such, it is possible that hiPSCs derived from authentic MSN progenitors could retain an authentic epigenetic memory of their previous cell type that enhances their differentiation towards an MSN fate, and in this thesis I aimed to test this hypothesis. In Chapter 3, I generated hiPSCs from the lateral ganglionic eminence (LGE), medial ganglionic eminence, and cortex of the human fetal brain, as well as fibroblast tissues. These hiPSCs were derived using a non-integrating virus, and from tissues collected from the same fetal donor to ensure these hiPSC lines were isogenic. I then validated these cells as pluripotent, and provided evidence that these hiPSCs could be defined by an epigenetic signature indicative of their tissue of origin. In Chapter 4, I explored the differentiation potential of these cells in vivo and in vitro. Here, I found some indication that hiPSCs derived from neural tissues undergo neuronal fate commitment at a faster rate than hiPSCs derived from non-neural tissues. However, I also found evidence that the epigenetic memory of hiPSCs derived from neural tissues may conflict with the differentiation methods used here, as generally these cells underperformed compared to hiPSCs derived from fibroblasts. As such, further research will be required to determine if this epigenetic memory can be used to enhance MSN differentiations. In Chapter 5, I conducted genome wide DNA methylation analysis on MSNs derived from these hiPSCs, and various controls including primary ganglionic eminence tissues. Here I found evidence that LGE derived hiPSCs may have an epigenome more similar to primary LGE tissue. However this similarity was found to be greatly overshadowed by a generally strong epigenetic difference between hPSC derived MSNs and the authentic primary tissues they are supposed to replace. The work contained in this thesis has important implications for the generation of MSNs from hPSCs, specifically regarding the importance of starting cell source and the understudied role of the epigenome in fate specification.

Item Type: Thesis (PhD)
Date Type: Completion
Status: Unpublished
Schools: Biosciences
Funders: Wellcome Trust
Date of First Compliant Deposit: 19 February 2020
Last Modified: 29 Mar 2021 09:50

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