Rejuvenating the aged cell through epigenetic modulation: defining culture conditions to reverse mesenchymal stromal cell (MSC) ageing

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Project rationale and importance: We have recently discovered epigenetic regulators that may be involved in MSC ageing. Our unpublished data using a short hairpin RNA (shRNA) library targeting 398 epigenetic enzymes indicates that silencing of specific epigenetic enzymes in aged/non-proliferating human MSCs (hMSCs) has the capacity to reverse growth arrest and re-establish cell proliferation. Interestingly, a large proportion of the identified epigenetic enzymes have associated small molecule (chemical/compound) modulators, which presents a unique opportunity to develop in vitro culture conditions that have the capacity to reverse hMSC ageing. Indeed, the reprogramming of somatic cells to pluripotency has taught us that at the cellular level it is possible to reset age to a 'ground state'. Careful manipulation of epigenetic state is also likely to make cells 'young again' without erasing their identity(4). This will ultimately lead to novel insights in how to reverse cell ageing and/or maintain cells in a youthful state, which will have significant impact and applications in regenerative medicine.Aim and objectives: This studentship will define the role of epigenetics in the ageing process of hMSCs, and create new technological advances towards the establishment of culture conditions to reverse cell ageing in vitro.Objective 1 To develop in vitro conditions with the capacity to modify hMSC ageing based on the control of epigenetic enzyme activity. Objective 2 To deliver a mechanistic understanding of the epigenetic control of hMSC ageing, hence identifying skeletal anti-ageing targets. Objective 3 To understand the heterogeneity of response to age reversal through epigenetic modulation by single cell RNA sequencing (scRNASeq).