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Materials-based strategies for epigenetic control of stem cell fate

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Title: Materials-based strategies for epigenetic control of stem cell fate
Authors: Morez, Constant
Item Type: Thesis or dissertation
Abstract: Direct reprogramming strategies for cell fate switching hold great promise for regenerative medicine. However, because of the strong stability provided by a cell's epigenome, the efficiency associated with such processes remains critically low. This study shows that the use of microgrooved substrates can dramatically alter a cell's epigenetic landscape. More specifically a significant disruption of the repressive heterochromatin is observed, characterised by a significant diminution of H3K27me3 and H3K9me3 levels and an increase in H3K4me3. In the specific case of cardiac direct programming through viral over-expression of key transcription factors, the use of these parallel microgrooves can significantly increase the number of induced cardiomyocyte-like cells generated. In addition microgrooved substrates can also stimulate histone acetylation, thereby increasing chromatin accessibility, and concomitantly stimulate sumoylation of the co-activator myocardin, thereby enhancing its cardiogenic capacity. Moreover, the alignment provided by the substrate can foster the establishment of organized sarcomeric structures, and therefore strengthen the maturation of the induced-cardiomyocytes. Lastly, the potential effect of the microgrooved substrate in neural progenitor differentiation is investigated. Interestingly, a strong epigenetic remodelling is also observed. However, apart from a notable induced histone hyper-acetylation, its characteristics are strikingly different, with notably a strong stimulation of the repressive H3K9me3 mark. Remarkably, neural progenitor differentiation triggered by the addition of soluble factors yielded significantly more neurons on the microgrooved substrates.
Content Version: Open Access
Issue Date: Sep-2015
Date Awarded: Mar-2016
URI: http://hdl.handle.net/10044/1/58204
DOI: https://doi.org/10.25560/58204
Supervisor: STEVENS, Molly M
Sponsor/Funder: British Heart Foundation
Department: Materials
Publisher: Imperial College London
Qualification Level: Doctoral
Qualification Name: Doctor of Philosophy (PhD)
Appears in Collections:Materials PhD theses

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