Background: 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. Methods and Principal Findings: 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 nao ¨ve 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 nao ¨ve hENPs is detrimental to functional recovery. Conclusions and Significance: 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 nao ¨ve-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.

/pdf/grafted-human-embryonic-progenitors-expressing-neurogenin-2-9kr3ov7gem.pdf

Grafted human embryonic progenitors expressing neurogenin-2 stimulate axonal sprouting and improve motor recovery after severe spinal cord injury.

OF THE DISSERTATION .................................................................. ii ACKNOWLEDGEMENT ....................................................................................... iv LIST OF TABLES .................................................................................................. x LIST OF ILLUSTRATIONS ................................................................................... xi LIST OF ABBREVIATIONS ................................................................................. xiii CHAPTER

The Fischer 344 spinal cord contusion model and effects of cyclosporin-A on the model

The immunological response to spinal cord injury: helpful or harmful?

Cell transplantation strategies are gaining increasing interest for spinal cord injury (SCI) with the objective of promoting spinal cord repair. To avoid allogenic graft rejection, an adequate immune suppression is required, and one of the most potent and commonly used immunosuppressives is cyclosporin A (CsA). In SCI, permanent sensory motor loss is combined with modifications of drug absorption, distribution and elimination. The objectives of this study were to thoroughly explore histological and functional outcomes of CsA treatment in a rat model of spinal cord compression. Experiments were carried out at the Institute for Neurosciences of Montpellier (France), the Integrative Biology of Neurodegeneration Laboratory (Spain) and in the Novartis Institutes for BioMedical Research (Switzerland) for CsA blood concentration determination. We first evaluated histological outcomes of CsA treatment on kidneys and spinal cord after SCI. We then investigated whether SCI modified CsA blood concentration. Finally, using behavioral analysis, we assessed the potential CsA impact on functional recovery. When spinal-cord-injured rats were treated with a CsA dose of 10 mg kg−1 per day, we observed deleterious effects on kidneys, associated with modifications of CsA blood concentration. Adding an antibiotic treatment reduced kidney alteration without modifying CsA blood concentration. Finally, we showed that CsA treatment per se modified neither functional recovery nor lesion extension. This study pinpoints the absolute requirement of careful CsA monitoring in the clinical setting for patients with SCI to minimize potential unexpected effects and avoid therapeutic failure.

/pdf/potential-adverse-effects-of-cyclosporin-a-on-kidneys-after-q71g545ir3.pdf

Potential adverse effects of cyclosporin A on kidneys after spinal cord injury

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Potential adverse effects of cyclosporin A on kidneys after spinal cord injury