Materials-based strategies for epigenetic control of stem cell fate

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.