Abstract
BackgroundSpinal 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 FindingsWith 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.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 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.
Highlights
Spinal cord injury (SCI) is a devastating pathology with currently no effective treatment of any symptom, that often leads to permanent loss of motor, sensory and autonomic functions
Grafting of naıve-human embryonic neural progenitors (hENPs) was found to worsen the outcome versus injured only animals, 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
Summary
Spinal cord injury (SCI) is a devastating pathology with currently no effective treatment of any symptom, that often leads to permanent loss of motor, sensory and autonomic functions (for review see [1,2]). Cell transplantation may be used in different non-exclusive ways to promote axonal regeneration and functional recovery after spinal traumatism: (1) to bring permissive molecules and/or trophic factors at the lesion level to enhance the regenerative capacity; (2) to provide a scaffold for the regeneration of severed axons; (3) to replace lost cells. In order to reconstruct the neuronal circuitry damaged by the lesion, transplantation of genetically modified cells expressing proneural factors is an appealing therapeutic strategy. 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
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