MAGFORCE4AXONGROWTH

Application of Mechanical Forces on Axon Growth Cones via Magnetic Nanoparticles to Enhance Axon Regeneration in Central Nervous System

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 Obiettivo del progetto (Objective)

'The lack of axon regeneration following spinal cord injury (SCI) diminishes patients’ quality of life and poses a significant economic burden on the society. This project aims to investigate the complex axon guidance mechanism following a SCI scenario by applying mechanical tension on the growth cones (GCs) of central nervous system (CNS) axons via novel magnetic nanoparticles that are functionalized with neuronal cell adhesion molecule. It is hypothesized that the complex interaction of chemical and physical guidance cues at the cytoskeletal (CSK) level can be modulated by mechanically activating specific signalling pathways, e.g., RhoGTPases. To test this hypothesis, mechanical tension will be applied to multiple GCs simultaneously, using a magnetic tweezers system integrated with a microfluidic culture device, which grants exclusive access to axonal areas. The effect of tension on axon outgrowth will be characterized as a function of chemical and mechanical environment, while examining the roles of Rho GTPase signalling and CSK structure in this mechanotransduction process. In essence, this project poses a biological hypothesis that can only be tested using a combination of sophisticated engineering methods. The results of this multidisciplinary project will provide a better understanding of axon elongation mechanisms and potentially become a promising therapeutic approach for SCI. The fellow is a mechanical / biomedical engineer with experience in microfluidic neuron culture and live cell microscopy; whereas the host is a world leader in single molecule biophysics. This project will not only contribute to the scientific competency of Europe by tackling a very relevant medical problem, but also provide the fellow an excellent opportunity to gain high quality scientific training and complementary skills, necessary to obtain an independent researcher position in the European Research Area.'

Introduzione (Teaser)

Spinal cord injury (SCI) and other neurodegenerative disorders could be resolved through nerve cell regeneration. EU-funded researchers investigated the use of growth cone migration to prompt axon regeneration.

Descrizione progetto (Article)

Axons are long slender projections of neurons and are responsible for transmitting information. Axonal growth capacity normally ends during foetal development and they do not regenerate after injury. External interventions have limited success as regenerating axons are unable to penetrate the stiff glial scar tissue formed after SCI.

Scientists of the MAGFORCE4AXONGROWTH project worked on elucidating relevant signalling pathways involved in modulating growth cone migration and axon regeneration. They synthesised magnetic nanoparticles to apply the requisite mechanical tension for the so-called axon-pulling experiments.

To begin with, researchers developed a microfluidic neuron culture device for primary cortical neurons obtained from embryonic mice. Axon growth cones were targeted through coating with antibodies specific for neuronal cell adhesion molecule (NCAM).

Researchers then developed and employed a magnetic tweezer-based microfluidic system for application of controlled force that mimics forces generated by neuronal growth cones. Applying chemical stimuli, the researchers assessed their effect on axon outgrowth and identified potential targets for therapy. The role of Semaphorin 3A and Netrin 1 was studied to understand the function of associated signal transduction pathways.

Results revealed that targeting the Rho kinase (ROCK) and Calpain signalling pathways would prove effective in combination with axon pulling experiments. Inhibition of the ROCK pathway along with application of magnetic forces redirected NCAM-mediated axonal growth towards the glial scar environment.

Project activities have opened up novel therapeutic avenues for treating SCI and neurodegenerative disorders. Their successful translation into clinical practice would improve the quality of life of such patients and significantly reduce the associated socioeconomic burdens.