Exploring the importance of mechanosensitivity for the peripheral nervous system

• Applicant: Professor Dr. Victor Shahin
• Subject Area: Developmental Neurobiology ; Developmental Biology
• Term: from 2018 to 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 407143946

Over the past few years a number of studies have demonstrated that diverse cell types are highly sensitive to the mechanical stiffness of their extracellular matrix (ECM) and that mechanosensitivity is physiologically crucial. The outcome of those studies has prompted the current view that mechanosensitivity acts in concert with biochemical cues to regulate the development, differentiation, maintenance and regeneration of cells. However, our understanding of mechanosensitivity remains insufficient. This is particularly the case for the peripheral nervous system (PNS). The PNS is exposed to substantial changes in the stiffness of its surroundings from early developmental stages to adulthood. Our insufficient PNS knowledge limits the success of treatment of common hereditary PNS neuropathies such as Charcot-Marie-Tooth 1A. The same is true for widespread PNS injuries, which often leave the afflicted persons with severe lifelong disabilities due to the lack of efficient and widely applicable nerve repair strategies. We hypothesise that ECM stiffness is important for the development, maintenance and regeneration of the PNS. To test this hypothesis we established two experimental models: embryonic mice dorsal root ganglions (DRGs) and primary co-culture of adult Schwann cells (SCs) and DRG neurons. We also designed an ECM-substrate with tunable stiffness. Our preliminary data demonstrate that embryonic DRGs, SCs and neurons are highly mechanosensitive. The goal of the present project is to comprehensively explore the implications of mechanosensititivity for the development, maintenance, regeneration and common hereditary diseases of the PNS. Both, wild-type and neuropathic animal models will be utilised. We believe that the essential basic biomedical and biophysical research of this project will significantly refine our PNS knowledge. In addition, it may set the stage for advancing the stagnating field of peripheral nerve repair, which presents a pressing medical need worldwide. This may be achieved by introducing mechanosenstivity as a new key parameter which should be included in the design of nerve grafts.

• DFG Programme: Research Grants