Evidence of axon connectivity across a spinal cord transection in rats treated with epidural stimulation and motor training combined with olfactory ensheathing cell transplantation

Abstract

Olfactory ensheathing cells (OECs) are unique glia that support axon outgrowth in the olfactory system, and when used as cellular therapy after spinal cord injury, improve recovery and axon regeneration. Here we assessed the effects of combining OEC transplantation with another promising therapy, epidural electrical stimulation during a rehabilitative motor task. Sprague-Dawley rats received a mid-thoracic transection and transplantation of OECs or fibroblasts (FBs) followed by lumbar stimulation while climbing an inclined grid. We injected pseudorabies virus (PRV) into hindlimb muscles 7 months post-injury to assess connectivity across the transection. Analyses showed that the number of serotonergic (5-HT) axons that crossed the rostral scar border and the area of neurofilament-positive axons in the injury site were both greater in OEC- than FB-treated rats. We detected PRV-labeled cells rostral to the transection and remarkable evidence of 5-HT and PRV axons crossing the injury site in 1 OEC- and 1 FB-treated rat. The axons that crossed suggested either axon regeneration (OEC) or small areas of probable tissue sparing (FB). Most PRV-labeled thoracic neurons were detected in laminae VII or X, and ~25% expressed Chx10, a marker for V2a interneurons. These findings suggest potential regeneration or sparing of circuits that connect thoracic interneurons to lumbar somatic motor neurons. Despite evidence of axonal connectivity, no behavioral changes were detected in this small-scale study. Together these data suggest that when supplemented with epidural stimulation and climbing, OEC transplantation can increase axonal growth across the injury site and may promote recovery of propriospinal circuitry.

Elucidating the Pivotal Neuroimmunomodulation of Stem Cells in Spinal Cord Injury Repair

“…The effects of transplanted OECs were observable after acute than delayed transplantation. However, current studies demonstrated that chronic transplants are still efficient in the improvement of recovery during SCI [97][98][99]. Nevertheless, some studies did not find any significant neuroprotective/regenerative role of OECs in SCI [82,[100][101][102].…”

Comparison of the effects of two therapeutic strategies based on olfactory ensheathing cell transplantation and repetitive magnetic stimulation after spinal cord injury in female mice

“…The second approach is based on promoting neuroregeneration by enhancing axonal regrowth or replacing lost cells (Ahuja et al., 2020). Indeed, based on several experimental paradigms, studies have reported that functional recoveries can be promoted after SCI in rodents by using neurotrophic factors infusion, cell transplantation, peripheral nerve graft, or combination of different treatments (Decherchi et al., 1997; Kanno et al., 2014; Thornton et al., 2018). In Humans this second approach is mainly based on cell transplantation.…”

Wireless Epidural Electrical Stimulation in Combination With Serotonin Agonists Improves Intraspinal Metabolism in Spinal Cord Injury Rats

“…While various complementary treatments such as neural stem cell transplantation, neural growth factor injection, and biomedical engineering (e.g., use of tissue scaffolds) can be administered to patients, satisfactory results have not been achieved for these treatments (2). Epidural electrical stimulation (EES) has been reported to restore rhythmic lower-limb movement (3), reorganize the cortico-reticulo-spinal circuit (4,5), and facilitate locomotor function via modulation of muscle spindle feedback circuits to preserve proprioceptive afferents (6,7). Compared with external assistance from an exoskeleton or physical assistance, EES improves the internal function of an injured spinal cord, thereby partially reestablishing the signal transmission between the brain and the injured spinal cord (4,5).…”

“…Epidural electrical stimulation (EES) has been reported to restore rhythmic lower‐limb movement (3), reorganize the cortico–reticulo–spinal circuit (4,5), and facilitate locomotor function via modulation of muscle spindle feedback circuits to preserve proprioceptive afferents (6,7). Compared with external assistance from an exoskeleton or physical assistance, EES improves the internal function of an injured spinal cord, thereby partially re‐establishing the signal transmission between the brain and the injured spinal cord (4,5).…”