Spinal Cord Transection: A Quantitative Analysis of Elements of the Connective Tissue Matrix Formed Within the Site of Lesion Following Administration of Piromen, Cytoxan or Trypsin

Abstract

Long-Evans hooded rats were cordotomized at the T-5 level and given either (1) cyclophosphamide (cytoxan), an immunosuppressive, (2) piromen, a bacterial polysaccharide-nucleic acid complex, (3) topical and systemic trypsin, or (4) no further specific treatment. Because of past and present controversy surrounding the proposed ability of these agents to promote spinal cord regeneration, a systematic study, employing light and electron microscopy, and quantitative methods in a single animal model, was done in order to re-evaluate the effects of each treatment upon the connective tissue matrix which forms in the defect left by transection. After an initial inflammatory reaction during the first week after surgery, the lesion zone is characterized either by areas of dense collagenous connective tissue with occasional fibroblasts and macrophages, or a loose areolar tissue with numerous sheets and cords of mesodermal cellular elements but minimal collagen. By 45 days postoperatively (dpo), axons supported by Schwann cells invade and become entangled in the loose connective tissue matrix. With longer postoperative survival, cysts appear craniad and caudad to the lesion and erode much of the scar together with viable neural tissue. Giving cytoxan or piromen did not result in any qualitative alteration of the scar matrix as evidenced by electron microscopy. Quantitative analysis revealed a slight reduction in the fibrous connective tissue component of the scar at 45--90 dpo, but this was transient when longer postoperative periods were studied. Trypsin caused a significant reduction in the amount of fibrous connective tissue with a concomitant increase in loose connective tissue and the appearance of a few distinctive, compact bundles of unmyelinated axons lacking Schwann cells. Consistent behavioral changes were not observed in any group which could distinguish them from the controls. Our results appear to contradict the findings of Matinian and Andreasian (1976) who reported return of normal sensori-motor function in 80% of their animals treated with topical and systemic trypsin. It is concluded that a major impediment to whatever longterm regenerative potential exists within the spinal cord is the lack of axonal guiding elements within the scar, but more importantly, the severe erosion of the remaining spinal cord due to cyst enlargement.

Endogenous Neurogenesis Replaces Oligodendrocytes and Astrocytes after Primate Spinal Cord Injury

“…Schwann cells extensively infiltrate sites of SCI in rodents (Matthews et al, 1979;Beattie et al,1997). Robust Schwann cell invasion of the perilesion region was also observed in the primate spinal cord based on p75 somal labeling in cells bearing the spindle-shaped morphology of Schwann cells (Fig.…”

Re‐establishment of direct synaptic connections between sensory axons and motoneurons after lesions of neonatal opossum CNS (Monodelphis domestica) in culture

“…1991) these results could indicate that prostaglandins suppress astrocyte reactivity and that VEGF could be produced by cells other than astrocytes. We therefore investigated whether a culture consisting mainly of fibroblasts with very few astrocytes, which resembles the cellular contents in the lesion area after spinal cord injury as previously described (Matthews et al . 1979; Berry et al .…”

Review: Manipulating the extracellular matrix and its role in brain and spinal cord plasticity and repair

“…It forms a more flexible triple helix which self‐polymerizes into a network and acts as a scaffold to integrate laminin and fibronectins into sheet‐like basement membrane; a matrix meshwork additionally interconnected via other glycoproteins and sulphated proteoglycans [19]. In the injured brain and spinal cord, alongside types I and III [20,21] collagen IV is the predominant fibrous element of scar tissue [22], where cells local to the lesion release protocollagen chains that self‐assemble into a dense network [23].…”

“…Following CNS injury the cell populations which contribute to a fibroblast phenotype are likely to be mixed, with severe parenchymal destruction causing invasion of populations not normally present within the CNS. Meningeal fibroblasts are established as contributing to scar formation, secreting collagen (particularly types I, III and IV [20,21]), fibronectin and laminin (reviewed in [147]). However, the precursors of cells which synthesize fibrotic matrix and the mechanisms behind their differentiation and recruitment is still debated.…”