Combinatorial strategies with Schwann cell transplantation to improve repair of the injured spinal cord

Abstract

The immediate effect of spinal cord injury (SCI) is a mechanical trauma that results in direct damage at the lesion site followed by secondary responses leading to loss of adjacent neurons and glia. Consequently, SCI leads to paralysis and loss of sensation below the level of the injury, altered autonomic responses and, frequently, the development of abnormal sensation and pain. Substantial endogenous remodeling of the spinal cord occurs [6] as axons begin to sprout and cells, including inflammatory, endothelial and Schwann cells (SCs), invade the injury site [34], likely contributing to spontaneous improvement observed in humans. Despite this endogenous repair, it is modest and functional improvements are limited [47;55]. Because treatment options are inadequate, additional therapeutic interventions are needed. Some strategies to repair the spinal cord are focusing on neuroprotection, regeneration, and/or tissue replacement. First, strategies should be designed to limit the secondary spread of damage to adjacent axons, neurons and glia. Second, strategies should promote axonal remodeling to maximize the function of spared tissue locally. Lastly, strategies are needed to promote long distance regrowth of damaged axons by reducing inhibition and/or providing permissive substrates and trophic molecules. The development of different injury models to mimic various aspects of human SCI, together with existing procedures to test behavioral recovery, have improved significantly our understanding of the pathophysiology of SCI and, importantly, have enabled investigation of a myriad of therapeutic interventions. Models are utilized to induce complete or incomplete SCI. Standardized devices are used to produce contusion or compression of the spinal cord, resulting in incomplete injuries with varying degrees of sparing depending upon the magnitude of the impact used [4;7;24;81]. Because standardization of the extent of injury is an essential component of these models, careful examination of the injury parameters and the behavioral recovery early after injury is essential to ensure the validity of the results observed in a specific therapeutic paradigm. Whereas contusion/compression models more accurately mimic the human injury, sparing of axons complicates the interpretation of axonal growth versus sparing. As a result, complete transection of the spinal cord is the favored model to study axonal regeneration. A cystic cavity usually forms after SCI, and it is walled off from the surrounding spared rim of white matter by a glial scar [6]. At the margins of the lesion, injured axons terminate in dystrophic endings, indicating thwarted axonal growth [74]. The presence of axons within trabeculae crossing the lesion implies that, when provided with an appropriate substrate, some axons will grow into the injury site despite the scar [6]. The use of permissive substrates such as cells, extracellular matrix proteins or biomaterials appears necessary to span the lesion. Also, cellular transplants can replace lost neurons and/or glia, enhance tissue preservation via neuroprotection and support axonal regeneration. In this chapter, we shall review experiments testing SC transplantation alone or in combination with known neuroprotective and neuroregenerative strategies. SCs from different sources will be described. Results of the use of SCs in three different injury models, complete transection of the spinal cord, lateral hemi-section and contusion, will be discussed. Whereas axonal regeneration is difficult to discern in the contusion model due to fiber sparing, it is relevant to human SCI in which there is usually some remaining tissue. Combinatorial approaches that have been successful to varying degrees will be highlighted; these generally involve combining neurotrophic factors (NTFs), scar modification, elevation of cAMP, reduction in myelin inhibition or olfactory ensheathing cell (OEC) transplantation with SCs. In addition, we shall discuss the rationale behind the success or failure of some combinatorial strategies and promising current treatments that may be amenable to combinatorial therapies.