Designing Glial-derived exosomes for use in nervous system repair

"Damage to the central nervous system (CNS), results in irreversible neurodegeneration and irrevocable loss of function.

This can occur following an accident, vascular event, or sports injury and is a major factor in natural aging. Axon regeneration in the CNS fails because glial cells form a scar tissue that is inhibitory for axon growth. To achieve targeted axon regeneration, combinatorial approaches involving cell transplantation to replace damaged cells and promote repair may be required. As such, olfactory ensheathing cells (OECs) have many advantages, because they are specialised glial cells that provide trophic factors and cellular bridges that promote and target growth of olfactory axons into the brain throughout life. Equally promising in terms of regenerative growth is the re-expression of integrin receptors which have been shown to be essential for axonal growth and pathfinding during development but are downregulated with maturation. Re-expression of integrin receptors in vivo has demonstrated promising results in sensory axon regeneration however data also indicates that integrins do not transport effectively from cell body to axon/growth cone within the main motor pathway, the corticospinal tract, thereby minimising their growth-promoting ability. Recently we have generated integrin-expressing exosomes from HEK293 cells and demonstrated that they induce significant outgrowth in cultured dorsal root ganglia neurons on inhibitory substrates. Therefore, this project aims to develop exosomes from a more physiological source, namely OECs, which can be modified to express growth-promoting receptors including integrins.

This PhD project will provide training in cellular assays to test the hypothesis that integrin-expressing exosomes derived from neural sources will induce significant growth of cultured primary neurons grown in the presence of inhibitory extracellular matrix and ex vivo in brain and spinal cord slice models."