Combining Schwann cell bridges and olfactory-ensheathing glia grafts with chondroitinase promotes locomotor recovery after complete transection of the spinal cord - PubMed (original) (raw)

Comparative Study

Combining Schwann cell bridges and olfactory-ensheathing glia grafts with chondroitinase promotes locomotor recovery after complete transection of the spinal cord

Karim Fouad et al. J Neurosci. 2005.

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.

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Figures

Figure 1.

Figure 1.

Experimental design for the cell grafting and cABC treatment after the removal of the thoracic 8 segment of the spinal cord.

Figure 2.

Figure 2.

Effectiveness of cABC application as demonstrated by the use of antibodies against either intact (1D1, CS-56) or digested (2B6) chondroitin sulfate. *p < 0.05.

Figure 3.

Figure 3.

Comparison of the open-field locomotion scores between the different treatment groups quantified with the BBB score (A) and by using the percentage of successful forelimb/hindlimb coupling (B). C, The time course of recovery shows treatment-induced benefits start to become apparent at 8 weeks after surgery. The dots represent the scores of single animals. *p < 0.05, **p < 0.01.

Figure 4.

Figure 4.

Video sequence from a rat treated with OEG and Schwann cell grafts as well as with cABC. Note the range of leg motion as well as the alternation between the forelimb and hindlimb movements. The panels are organized in rows from left to right.

Figure 5.

Figure 5.

Sensory testing using von Frey hairs at the base of the tail shows increased responsiveness in all of the treated groups. *p < 0.05.

Figure 6.

Figure 6.

A, 5-HT-positive fibers were found to grow into the caudal spinal cord. The quantification of these fibers in the caudal spinal cord is illustrated in B. As documented in C, there was no correlation between individual functional recovery and the number of 5-HT-positive fibers in the caudal spinal cord. *p < 0.05.

Figure 7.

Figure 7.

Significantly greater numbers of peripheral-myelinated axons (arrow) are present within the Schwann cell bridge after digestion of CSPGs with chondroitinase ABC. Animals with grafts only (A) and animals with grafts and cABC (B) are shown. Scale bar, 150 μm.

Figure 8.

Figure 8.

Counts of myelinated axons in the middle of the bridge showed a significant (p < 0.01) increase (A) in the group with grafts and cABC. B, The number of blood vessels in the bridge was not different between the groups. C, There was a significant correlation (_r_2 = 0.63) between individual functional recovery and the number of myelinated axons.

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