Combinatory repair strategy to promote axon regeneration and functional recovery after chronic spinal cord injury

Abstract

Eight weeks post contusive spinal cord injury, we built a peripheral nerve graft bridge (PNG) through the cystic cavity and treated the graft/host interface with acidic fibroblast growth factor (aFGF) and chondroitinase ABC (ChABC). This combinatorial strategy remarkably enhanced integration between host astrocytes and graft Schwann cells, allowing for robust growth, especially of catecholaminergic axons, through the graft and back into the distal spinal cord. In the absence of aFGF+ChABC fewer catecholaminergic axons entered the graft, no axons exited, and Schwann cells and astrocytes failed to integrate. In sharp contrast with the acutely bridge-repaired cord, in the chronically repaired cord only low levels of serotonergic axons regenerated into the graft, with no evidence of re-entry back into the spinal cord. The failure of axons to regenerate was strongly correlated with a dramatic increase of SOCS3 expression. While regeneration was more limited overall than at acute stages, our combinatorial strategy in the chronically injured animals prevented a decline in locomotor behavior and bladder physiology outcomes associated with an invasive repair strategy. These results indicate that PNG+aFGF+ChABC treatment of the chronically contused spinal cord can provide a permissive substrate for the regeneration of certain neuronal populations that retain a growth potential over time, and lead to functional improvements.

Plasticity Induced Recovery of Breathing Occurs at Chronic Stages after Cervical Contusion

“…Previous reports typically describe specific fibre type loss at the site of injury or behavioural deficit rather than the specific lesion volume to show consistency within their model or effect of ChABC treatment. 30,32,[51][52][53] . However, hemisection studies have similarly shown no effect of ChABC on lesion size.…”

“…8,15 Our observations that ChABC brought about the increased serotonergic fibre innervation at the PMP correlate with other models of contusive SCI showing that application of the enzyme increases serotonergic sprouting and functional activity. [30][31][32][33]42,51 Of course, it is likely that other mechanisms of recovery are additionally functioning. For example, the recruitment of V2a interneurons has been shown critical in rat and mouse models of cervical SCI to the promotion of respiratory function.…”

“…[27][28][29][30] Indeed, application of the enzyme most commonly shows significant effects upon functional activity after contusion injury when acting in combination with other treatments. 29,[31][32][33] However, these data were collected when assessing motor systems that demonstrate little endogenous plasticity after trauma. Contrary to this, the respiratory motor system is capable of plastic alteration and reorganisation following trauma.…”

Long non‐coding RNAs in the spinal cord injury: Novel spotlight

“…Glia could be activated within 1 day (microglial activation) and persist for months or even years (astrogliosis) after SCI. [38][39][40][41] As for different cellular subsets (eg M1 vs M2 phenotypes) 42 and Adm (Adrenomedullin), both of which have been reported to promote astrogliosis in the spinal cord, 46,47 indicating that lncSCIR1 might have a role in regulating astrocytes. Indeed, knockdown of lncSCIR1 was sufficient to promote the migration and proliferation of cultured astrocytes.…”

Single vs. Combined Therapeutic Approaches in Rats With Chronic Spinal Cord Injury

“…If used independently, the benefits of the above-mentioned strategies seem insufficient to be translated to patients, but several experimental studies have shown that combined therapies may produce a greater benefit (11)(12)(13)(14). In fact, recently, we reported on the additive morphofunctional effect of combining PPN and BMSCs in a model of spinal cord transection (15).…”