Researchers report the successful use of a novel therapeutic strategy to enhance forelimb recovery in mice with chronically injured spinal cords. The findings were presented by Hidenori Suzuki (Department of Orthopaedics, Yamaguchi University graduate school of medicine, Ube, Japan) at the 45th annual meeting of the Cervical Spine Research Society (30th November – 2nd December, Florida, US), where Suzuki was awarded 1st place in the basic science award.
Traumatic spinal cord injuries affect millions of people worldwide. While the majority are in the chronic phase of their injury, most research focuses on the acute phase of spinal cord injuries, as glial scarring is not yet well established. The glial scar acts as both a physical and biochemical barrier to inhibit neural regeneration in the chronic injury phase.
Detailing the mechanism by which glial scarring hinders neurological recovery, Suzuki explains: “After spinal cord injury, astrocytes activate, proliferate, and migrate to the perilesional region where they form a dense interwoven network of processes and deposit chondroitin sulfate proteoglycans (CSPG) into the extracellular matrix.”
“Dystrophic axons surround the injury epicenter becoming trapped in this dense meshwork of scar tissue. The axonal failure is mediated by both the physical proteoglycan barrier and biochemical signaling within axon growth cones induced by interaction with sulfated CSPGs.”
However, this study offers hope for the possibility of neuronal regeneration, with subsequent recovery of some motor function, in chronically injured spinal cord patients. These findings therefore have important clinical implications for the vast majority of patients who are in the chronic phase of their injuries where even small improvements in hand motor function can have tremendous impacts on their quality of life.
Suzuki and colleagues utilised a novel, combinatorial treatment strategy. The team used Chondroitinase ABC (ChABC) pretreatment to positively modify the injured microenvironment. ChABC is an enzyme that, when injected into the lesion site, degrades the inhibitory CSPGs that build up within the glial scar matrix.
Suzuki told Spinal News International: “Despite the need, one of the greatest challenges in developing an effective therapy for chronic spinal cord injury has been the inhibitory microenvironment of the injured spinal cord. ChABC is a bacterially-derived enzyme capable of degrading CSPGs, and has been successfully used as a standalone treatment in animal models of spinal cord injury.”
After one week of ChABC delivery by an intrathecal osmotic pump, induced pluripotent stem cell derived neural stem cells (iPSC-NSCs) were transplanted into the injury site.
Total numbers of acetylcholinergic neurons, a key population responsible for motor function, were significantly higher in the combinatorial treatment group. Several transplant-derived neurons appeared to be myelinated with myelin basic protein+, “highlighting the integration of transplanted cells and their ability to form appropriate nascent networks”, as Suzuki and colleagues report in the journal PLoS One.
Functional synapses also formed in vivo following combined treatment. The transplant-derived neurons can integrate into complex local circuits, with both inhibitory and excitatory components.
Describing the results of the study, Suzuki comments: “This study demonstrates a clear survival advantage for iPS-NSC grafted into ChABC pretreated animals (7.88 ± 1.60% vs 2.44 ± 1.04%), suggesting that the harsh chronic spinal cord injury niche can be ‘unlocked’ to be more conducive to regeneration.”
“Importantly, while greater numbers of exogenous cells survived, the differentiation profile remained unchanged with progeny of all three neuroglial lineages being found throughout the epicenter and perilesional regions.”
The study also evidenced enhanced behavioural recovery with this novel synergic treatment. Both forelimb grip strength and locomotor function recovery were significantly improved following the use of ChABC and transplanted stem cells.
This is the first report of motor function recovery and local circuit reconstruction following combinatorial treatment in spinal cord injury, though cell therapy and ChABC injection have been used experimentally in the acute and subacute phase of spinal cord injury.
The experimenters used a clinically relevant clip-contusion model of spinal cord injury in mice, which closely mimics the pathophysiology in humans.
Speaking of possible clinical ramifications, Suzuki comments: “iPS-NPCs are the most promising candidate in clinical use for the regeneration therapy for spinal cord injury. The next step will be to adapt this treatment protocol to translationally-relevant human cell lines, while exploring longer experimental timelines to assess safety and graft integration.”
“This study was designed for clinical use in the near future. That’s the reason we used a clinically-relevant neurological exam (in vivo electrophysiological and behavioural data).”
Further work is needed to progress beyond studies in mice, but Suzuki is optimistic about this novel treatment: “we just showed there is hope for a new therapy for chronic spinal cord injury patients.”