Authors: A. GUIJARRO-BELMAR, M. VISKONTAS, X. BO, D. SHEWAN, W. HUANG
Spinal cord injury (SCI) is a highly debilitating trauma affecting millions of patients worldwide with no cure. The challenges for spinal repair include a lack of intrinsic capacity for adult CNS neurons to regrow post injury and the inhibitory physical and chemical barriers formed at the lesion site. One of the most promising new avenues for spinal repair is to combine novel axon growth-promoting and tissue-engineering strategies, thus creating a permissive and encouraging environment for injured spinal nerve processes to regrow.
Elevated levels of cAMP have been shown to promote injured CNS neurons to sprout and extend neurites, even in the presence of growth inhibitory molecules including chondroitin sulphate proteoglycans (CSPGs). cAMP is now known to signal via Epac, a guanine nucleotide exchange factor, which has two isoforms, Epac1 and Epac2, with the latter expressed mainly in postnatal neural tissue. By using primary neuronal cultures, immunocytochemistry and lentiviral tools, we herein demonstrate that specific activation of Epac2 significantly enhances neurite outgrowth of cultured postnatal rat cortical neurons and is able to overcome the inhibitory effects of CSPGs and mature activated astrocytes on cortical neuron growth in vitro.
With the aim to find an effective combinatorial strategy, we have further explored the suitability of a novel self-assembling hydrogel for spinal repair. The gel is a synthetic polymer with 3-D nanostructured networks that are similar to native extracellular matrix and can be functionalised with growth-promoting drugs. We show that this gel has appropriate stiffness, biocompatibility and biodegradation properties to promote cultured postnatal cortical neuron growth. By using an ex vivo model that mimics the in vivo environment after spinal injury, we demonstrate that the gel incorporated with a specific Epac2 agonist promotes significantly more axon regrowth than gel alone and without gel. By using a partial transection model of spinal injury, we further demonstrate that the spinal injured rats receiving implantation of the gel incorporated with the Epac2 agonist have much better locomotor function recovery than those rats having gel only implantation.
Our results demonstrate the potential of combining Epac2 activation with novel 3-D growth-supporting hydrogels to promote axon regrowth, thus contributing to new methods for spinal repair. Future studies will examine the efficacy of this combined strategy in a clinically relevant contusion model of spinal injury.
Grant Support: Nathalie Rose Barr Studentship. International Spinal Research Trust
*A. GUIJARRO-BELMAR1, M. VISKONTAS1, X. BO2, D. SHEWAN1, W. HUANG1;
1Univ. of Aberdeen, Aberdeen, United Kingdom; 2Ctr. for Neurosci. and Trauma, Queen Mary Univ. of London, London, United Kingdom. A novel biomaterial-based Epac targeting approach to promote spinal cord repair. Program No. 213.04. 2018 Neuroscience Meeting Planner. San Diego, CA: Society for Neuroscience, 2018. Online.