The collagenous wound healing scar in the injured central nervous system inhibits axonal regeneration.

Following traumatic injuries of the central nervous system (CNS) a wound healing scar, resembling the molecular structure of a basement membrane and mainly composed of Collagen type IV and associated glycoproteins and proteoglycans, is formed. It is well known that CNS fibers poorly regenerate after traumatic injuries. In this article we summarize data showing that prevention of collagen scar formation enables severed axons in brain and spinal cord to regrow across the lesion site and to elongate in uninjured CNS tissue. We observed that regenerating fibers grow back to their former target where they develop chemical synapses, become remyelinated by resident oligodendrocytes and conduct action potentials.

Collagen matrix in spinal cord injury.

The fibrous scar that develops after central nervous system (CNS) injury is considered a major impediment for axonal regeneration. It consists of a dense collagen IV meshwork, which serves as a binding matrix for numerous other extracellular matrix components and inhibitory molecules like proteoglycans and semaphorins, but also growth-promoting factors. Inhibition of collagen matrix formation in brain and spinal cord lesions leads to axonal regeneration and functional recovery, although collagen IV per se is not inhibitory for axonal outgrowth. This review focuses on the molecular properties of the collagen IV matrix and its interactions with various molecules that are expressed after CNS lesion. Moreover, studies on collagen expression and matrix formation after injury of regenerating versus non-regenerating nervous systems are reviewed. Major differences in collagen deposition in the CNS and the peripheral nervous system (PNS) and differences in specific cell responses to extracellular matrix deposition in the lesion area are discussed. Therapeutic treatments aiming at suppression of fibrous scarring have been shown to promote axon regeneration in various lesion paradigms of the mammalian CNS.

Suppression of fibrous scarring in spinal cord injury of rat promotes long-distance regeneration of corticospinal tract axons, rescue of primary motoneurons in somatosensory cortex and significant functional recovery.

Traumatic injury of the central nervous system results in formation of a collagenous basement membrane-rich fibrous scar in the lesion centre. Due to accumulation of numerous axon-growth inhibitory molecules the lesion scar is considered a major impediment for axon regeneration. Following transection of the dorsal corticospinal tract (CST) at thoracic level 8 in adult rats, transient suppression of collagenous scarring in the lesion zone by local application of a potent iron chelator and cyclic adenosine monophosphate resulted in the delay of fibrous scarring. Treated animals displayed long-distance growth of CST axons through the lesion area extending for up to 1.5-2 cm into the distal cord. In addition, the treatment showed a strong neuroprotective effect, rescuing cortical motoneurons projecting into the CST that normally die (30%) after thoracic axotomy. Further, anterogradely traced CST axons regenerated through both grey and white matter and developed terminal arborizations in grey matter regions. In contrast to controls, injured animals receiving treatment showed significant functional recovery in the open field, in the horizontal ladder and in CatWalk locomotor tasks. We conclude that the fibrous lesion scar plays a pivotal role as a growth barrier for regenerating axons in adult spinal cord and that a delay in fibrotic scarring by local inhibition of collagen biosynthesis and basement membrane deposition is a promising and unique therapeutic strategy for treating human spinal trauma.