Functional regeneration of respiratory pathways after spinal cord injury

Abstract

Spinal cord injuries (SCI) often occur at the cervical level above the phrenic motor pools, which innervate the diaphragm. Unfortunately, the untoward effects of impaired breathing are a leading cause of SCI-related death, underscoring the importance of developing strategies to restore respiratory activity. Here we show that after cervical SCI, there is upregulation of the perineuronal net (PNN) associated chondroitin sulfate proteoglycans (CSPGs) around phrenic motor neurons. Digestion of these potently inhibitory extracellular matrix molecules with Chondroitinase ABC (ChABC) can, by itself, promote plasticity of spared tracts and restore limited activity to the paralyzed diaphragm. However, when combined with application of a peripheral nerve autograft, ChABC treatment results in lengthy regeneration of serotonergic axons and other bulbospinal fibers with remarkable recovery of diaphragm function. Following recovery and initial transection of the bridge, there occurs an unusual, overall increased tonic diaphragmatic EMG activity, suggesting considerable remodeling of spinal cord circuitry after regeneration. This is followed by complete elimination of the restored activity proving that regeneration is critical for the return of function. Overall, these experiments present a way to profoundly restore function of a single muscle following debilitating CNS trauma, through both plasticity of spared tracts and regeneration of essential pathways.

Canine olfactory ensheathing cells from the olfactory mucosa can be engineered to produce active chondroitinase ABC

“…However, injured axons are unable to regenerate across the site of injury in the central nervous system because of the presence of an array of inhibitory cues present within the scar (For a review, see 5,6), in particular chondroitin sulphate proteoglycans (CSPGs) (7)(8)(9)(10). Digestion of CSPGs with the bacterial enzyme chondroitinase ABC (ChABC), following local delivery to the spinal cord, has led to axon regeneration, plastic neuronal rearrangements and functional recovery following section or crush injury in laboratory animal SCI models (11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21). Encouragingly, these findings have also been found using clinically relevant contusive injury rodent models (22,23) and large animal models such as cats and squirrel monkeys (19,24,25).…”

Conditional Sox9 ablation reduces chondroitin sulfate proteoglycan levels and improves motor function following spinal cord injury

“…Enzymatic digestion of the chondroitin sulfate side chains found on all CSPGs by intrathecal chondroitinase ABC treatment resulted in increased regeneration of ascending and descending tracts after SCI (Bradbury et al, 2002). The combination of chondroitinase ABC with peripheral nerve grafts (Alilain et al, 2011;Houle et al, 2006), rehabilitation (Garcia-Alias et al, 2009;Wang et al, 2011), or neural precursor cell transplantation (Karimi-Abdolrezaee et al, 2010) have all led to improved axonal regeneration and recovery.…”

Spinal cord injury models: a review

“…The technique has also recently been used to investigate nerve grafting, a potentially promising surgical treatment for SCI. 42 In addition, given that hemisection results in a less severe injury than complete transection, postoperative animal care is easier. 40 However, it is more difficult to inflict a consistent injury with a partial transection model, and it can be difficult to determine whether the target tract is completely severed.…”