Combining Schwann Cell Bridges and Olfactory-Ensheathing Glia Grafts with Chondroitinase Promotes Locomotor Recovery after Complete Transection of the Spinal Cord

Abstract

Numerous obstacles to successful regeneration of injured axons in the adult mammalian spinal cord exist. Consequently, a treatment strategy inducing axonal regeneration and significant functional recovery after spinal cord injury has to overcome these obstacles. The current study attempted to address multiple impediments to regeneration by using a combinatory strategy after complete spinal cord transection in adult rats: (1) to reduce inhibitory cues in the glial scar (chondroitinase ABC), (2) to provide a growth-supportive substrate for axonal regeneration [Schwann cells (SCs)], and (3) to enable regenerated axons to exit the bridge to re-enter the spinal cord (olfactory ensheathing glia). The combination of SC bridge, olfactory ensheathing glia, and chondroitinase ABC provided significant benefit compared with grafts only or the untreated group. Significant improvements were observed in the Basso, Beattie, and Bresnahan score and in forelimb/hindlimb coupling. This recovery was accompanied by increased numbers of both myelinated axons in the SC bridge and serotonergic fibers that grew through the bridge and into the caudal spinal cord. Although prominent descending tracts such as the corticospinal and reticulospinal tracts did not successfully regenerate through the bridge, it appeared that other populations of regenerated fibers were the driving force for the observed recovery; there was a significant correlation between numbers of myelinated fibers in the bridge and improved coupling of forelimb and hindlimb as well as open-field locomotion. Our study tests how proven experimental treatments interact in a well-established animal model, thus providing needed direction for the development of future combinatory treatment regimens.

Cotransplant of neural stem cells and NT-3 gene modified Schwann cells promote the recovery of transected spinal cord injury

“…21 Briefly, slices were rinsed three times (5 min each time) with 0.01 M PBS (pH 7.4) followed by incubation in X-gal reagent (Molecular Probes, 1 mg/ml final concentration) with X-gal mixer (35 mM K 3 Fe(CN) 6 , 35 mM K 4 Fe(CN) 6 , 2 mM MgCl 2 in PBS) at 371C overnight. Before coverslipped, the slices were counterstained with neutral red.…”

“…[4][5][6] It was demonstrated that SCs could synthesize many kinds of neurotrophic factors, cell adhesion, and extracellular matrix molecules. All of these factors are prerequisites for the survival and axonal regeneration of damaged neurons.…”

International spinal research trust research strategy. III: A discussion document

“…For example, reducing inhibitory cues of the scar tissue with chondroitinase ABC and providing a Schwann cell bridge in combination with olfactory ensheathing cells promotes greater functional recovery in a rat model than these treatments individually. 61 Gene therapy The first viral vectors used to express a therapeutic gene in the nervous system were imperfect because they evoked an immune response. These problems inspired the development of improved 'minimal' vectors based on adeno-associated virus and lentivirus.…”

“…Therefore, it seems reasonable to anticipate that therapies that are directed at one specific injury mechanism are likely to have limited overall efficacy, and that combining potential therapies might achieve a greater benefit and increase recovery. 61 Some published studies have combined the use of cell transplantation and plasticity-promoting drugs to provide proof-of-principle of this concept. It is likely that more effective combinations are possible, and combination therapy is likely to be a cornerstone of future strategies following SCI.…”

Clinical canine spinal cord injury provides an opportunity to examine the issues in translating laboratory techniques into practical therapy

“…24 However, there are many other experimental models of SCI and each has advantages and disadvantages in investigating various aspects of lesion development, recovery mechanisms and putative therapeutic interventions. Thus, complete spinal cord transection often provides the most unequivocal information regarding axonal regeneration, [25][26][27] and spinal hemisection, or more localised sharp spinal injuries, provides invaluable data regarding plastic mechanisms of recovery of function. 28,29 Similarly, attempts to understand the cellular and molecular events that follow clinical SCI are most reliant on contusion models (see above) that mimic the events that occur commonly in human SCI.…”