Mechno-regulation of genome function to direct stem cell fate

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A growing number of pathological conditions are associated with inappropriate or defective cellular sensing of their mechanical environment. Adult mesenchymal stem cells (MSCs) provide a promising cell source for many regenerative therapies although relatively little is known concerning the mechanisms through which mechanical stimuli are transduced into regulatory signals within the cell.Cellular behaviour is largely regulated by gene expression, which is directed from within the nucleus through transcription of DNA. DNA is packaged within the nucleus as chromatin. The compaction state of chromatin impacts gene transcription, and can result in gene silencing. This compaction state is controlled by a number of histone proteins, and is further influenced by the nuclear lamina, a fibrillar matrix within the nucleus lining the inner nuclear membrane. This controls gene silencing in DNA situated near the edge of the nucleus, and is connected via a complex of proteins (the LINC complex) to the cytoskeleton; the cells skeleton which provides the cell with structure. During stem cell differentiation, the nucleus has been shown to remodel, with alterations to nuclear stiffness and the nuclear lamina; potentially influencing gene transcription. Furthermore, if the nucleus stiffness and the connections between the nucleus and cytoskeleton, the LINC complex, are modulated, force transfer to the nucleus may be altered.This project will address the concept that the nucleus acts as a sensor for mechanical stimuli. It will also address the hypothesis that the role of the nucleus as a mechanosensor changes as a cell progresses along its differentiation route. We will investigate the mechanisms through which mechanical stimuli can induce changes in nuclear organisation and stem cell differentiation. By fully characterising changes in the mechanical properties, protein composition, nuclear architecture and epigenetic signature of biophysically stimulated MSCs as they undergo differentiation, we will identify key pathways responsible for the alteration of cellular mechanosensitivity. These can then be targeted to repair defective mechanosensitivity in diseased or aged cells.The results of this work will have far reaching implications for our understanding of how cells respond to mechanical stimulation, and will impact strategies for cell based regenerative medicine and musculoskeletal repair.