Mechanobiology is an emerging field which studies how physical forces and changes can contribute to cell differentiation, tissue formation and diseases. These forces are applied on cells through the local variations between neighbouring cells and the extracellular matrix. Notably, cell?cell and cell-extracellular matrix mechanical stimuli can stimulate electrochemical responses, the rearrangement of cytoskeletal structures and the regulation of gene expression. Schwann cells, the myelinating cells of the peripheral nervous system, are required for the function and health of the peripheral nervous system. Schwann cells also have a critical role in the regenerative potential of the peripheral nervous system, but very little is known about how Schwann cells sense axonal injury. We demonstrated that Schwann cells are exquisitely sensitive to alterations in the elasticity of the extracellular matrix; and that Schwann cell differentiation and myelination during the peripheral nervous system development depend on the transduction of mechanical stimuli by YAP and TAZ. Yet, it is unknown what are the signalling upstream and downstream YAP and TAZ in Schwann cells and if YAP and TAZ are also required for Schwann cell differentiation and remyelination after peripheral nerve injury. Here we will investigate if the transduction of mechanical stimuli in Schwann cells is critical to stimulate myelination and improve peripheral nerve regeneration. Our objectives are to determine if it is possible to manipulate Schwann cells mechanically to improve myelination, with therapeutic implications (Aim 3) and to discover new components of the mechanotransduction pathways upstream (Aim1) and downstream (Aim 2) of YAP and TAZ. Studying myelination through the mechanotransducers YAP and TAZ has potential to advance the field by identifying the therapeutic importance of Schwann cell and cellular mechanobiology and may reveal novel targets or mechanisms for myelin formation and peripheral nerve regeneration in neuropathies molecular.
We are proposing a to study how mechanical stimuli can stimulate myelination and improve peripheral nerve regeneration after injury. If our working model is validated, this proposal will define the importance of mechanobiology in peripheral nerves and may reveal novel therapeutic targets for myelin diseases and for peripheral nerve regeneration.
