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Title: Materials-based strategies for epigenetic control of stem cell fate
Author: Morez, Constant
ISNI:       0000 0004 7228 3425
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2016
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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.
Supervisor: Stevens, Molly M. ; Schneider, Michael D. Sponsor: British Heart Foundation
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral