Olfactory Ensheathing Cell Transplantation Combined With Electrical Epidural Stimulation as a Long-Term Treatment for Severe Spinal Cord Injury in Female Fischer 344 Rats.

Following severe spinal cord injury (SCI), transplanted olfactory ensheathing cells (OECs) reduce inhibitory factors and promote axonal outgrowth at the lesion site to help reestablish the circuit connectivity needed for functional recovery. Another promising therapy, electrical epidural stimulation, also helps to reestablish connectivity but targets the caudal spinal cord. This study asked if the combination of OEC transplantation and administration of electrical epidural stimulation during climb training would improve recovery. Inbred Fischer 344 rats received a severe-to-complete SCI and a two-week delayed transplant of OECs, media, or fibroblasts. Rats received electrical epidural stimulation while performing a climbing task 3 times/week. To evaluate connectivity across the injury site, we injected a transsynaptic retrograde tracer GFP-pseudorabies virus into the tibialis anterior of one hindlimb and RFP-pseudorabies virus into the soleus of the other. Scores on the BBB locomotor test improved for all groups over time, but no behavioural differences were detected. Importantly, the GFP-labelled OECs and fibroblasts survived in the injury site for 5.5-6.5 months. OEC treatment greatly increased the density of serotonergic and neurofilament-positive axons in the lesion core versus controls. The percent of neurofilament-positive axons associated with myelin proteins was greater in OEC- than in media-treated rats. We also found evidence of pseudorabies virus-infected propriospinal neurons that express the transcription factor Chx10 above the injury site and some were cholinergic and dually-labelled from antagonistic muscles. These results provide evidence that OEC transplantation combined with electrical epidural stimulation may be a beneficial treatment for severe SCI.