Strategies for regeneration and repair in spinal cord traumatic injury.
ABSTRACT Spinal cord injury is frequently followed by the loss of supraspinal control of sensory, autonomic and motor functions at the sublesional level. In order to enhance recovery in spinal cord-injured patients, we have developed three fundamental strategies in experimental models. These strategies define in turn three chronological levels of postlesional intervention in the spinal cord. Neuroprotection soon after injury using pharmacological tools to reduce the progressive secondary injury processes that follow during the first week after the initial lesion. This strategy was conducted up to clinical trials, showing that a pharmacological therapy can reduce the permanent neurological deficit that usually follows an acute injury of the central nervous system (CNS). A second strategy, which is initiated not long after the lesion, aims at promoting axonal regeneration by acting on the main barrier to regeneration of lesioned axons: the glial scar. Finally a mid-term substitutive strategy is the management of the sublesional spinal cord by sensorimotor stimulation and/or supply of missing key afferents, such as monoaminergic systems. These three strategies are reviewed. Only a combination of these different approaches will be able to provide an optimal basis for potential therapeutic interventions directed to functional recovery after spinal cord injury.
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ABSTRACT: Spinal cord injury (SCI) is a widely spread pathology with currently no effective treatment for any symptom. Regenerative medicine through cell transplantation is a very attractive strategy and may be used in different non-exclusive ways to promote functional recovery. We investigated functional and structural outcomes after grafting human embryonic neural progenitors (hENPs) in spinal cord-lesioned rats. With the objective of translation to clinics we have chosen a paradigm of delayed grafting, i.e., one week after lesion, in a severe model of spinal cord compression in adult rats. hENPs were either naïve or engineered to express Neurogenin 2 (Ngn2). Moreover, we have compared integrating and non-integrating lentiviral vectors, since the latter present reduced risks of insertional mutagenesis. We show that transplantation of hENPs transduced to express Ngn2 fully restore weight support and improve functional motor recovery after severe spinal cord compression at thoracic level. This was correlated with partial restoration of serotonin innervations at lumbar level, and translocation of 5HT1A receptors to the plasma membrane of motoneurons. Since hENPs were not detectable 4 weeks after grafting, transitory expression of Ngn2 appears sufficient to achieve motor recovery and to permit axonal regeneration. Importantly, we also demonstrate that transplantation of naïve hENPs is detrimental to functional recovery. Transplantation and short-term survival of Ngn2-expressing hENPs restore weight support after SCI and partially restore serotonin fibers density and 5HT1A receptor pattern caudal to the lesion. Moreover, grafting of naïve-hENPs was found to worsen the outcome versus injured only animals, thus pointing to the possible detrimental effect of stem cell-based therapy per se in SCI. This is of major importance given the increasing number of clinical trials involving cell grafting developed for SCI patients.PLoS ONE 01/2010; 5(12):e15914. · 3.73 Impact Factor
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ABSTRACT: INTRODUCTION: Thanks to the Internet, we can now have access to more information about spinal cord repair. Spinal cord injured (SCI) patients request more information and hospitals offer specific spinal cord repair medical consultations. OBJECTIVE: Provide practical and relevant elements to physicians and other healthcare professionals involved in the care of SCI patients in order to provide adequate answers to their questions. METHOD: Our literature review was based on English and French publications indexed in PubMed and the main Internet websites dedicated to spinal cord repair. RESULTS: A wide array of research possibilities including notions of anatomy, physiology, biology, anatomopathology and spinal cord imaging is available for the global care of the SCI patient. Prevention and repair strategies (regeneration, transplant, stem cells, gene therapy, biomaterials, using sublesional uninjured spinal tissue, electrical stimulation, brain/computer interface, etc.) for the injured spinal cord are under development. It is necessary to detail the studies conducted and define the limits of these new strategies and benchmark them to the realistic medical and rehabilitation care available to these patients. CONCLUSION: Research is quickly progressing and clinical trials will be developed in the near future. They will have to answer to strict methodological and ethical guidelines. They will first be designed for a small number of patients. The results will probably be fragmented and progress will be made through different successive steps.Annals of physical and rehabilitation medicine 05/2009;
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ABSTRACT: We have successfully removed an existing glial scar in chronically contused rat spinal cord using a rose Bengal-based phototoxic method. The purpose of this study is to examine if scar ablation benefits the anatomical recovery by cell/tissue transplantation, and thus provides a more permissive physical and biochemical environment for axonal growth, which may lead to functional recovery. Immediately after scar ablation, we transplanted lamina propria (LP) of the olfactory mucosa alone or in combination with cultured olfactory ensheathing cells (OEC) into the lesion cavity 6 weeks after contusion injury (NYU impactor device, 25 mm height setting) at spinal cord segment T10 of adult female Long-Evans rats. Sixteen weeks after scar ablation and transplantation, we found that the initial repaired tissue significantly expanded, companied by remarkable reduction or disappearance of the lesion cavity and integration of repaired tissue with the spared tissue, thus resulting in histological repair of damaged cord tissue at the injury epicenter. Glial scar reformation was effectively prevented after ablation due to the tissue repair. In addition, at the injury epicenter P0 (myelin glycoprotein P-zero)-positive myelination formed by Schwann cells, which are known to myelinate regenerating and demyelinated axons, were significantly increased in number compared with the control animals. However, when evaluated with BBB open-field scale a significant improvement of locomotor function was not observed in this study; the possible reasons were discussed.Brain research 07/2011; 1399:1-14. · 2.46 Impact Factor