Grafted Human Embryonic Progenitors Expressing Neurogenin-2 Stimulate Axonal Sprouting and Improve Motor Recovery after Severe Spinal Cord Injury

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.

Conditioned Medium from Bone Marrow-Derived Mesenchymal Stem Cells Improves Recovery after Spinal Cord Injury in Rats: An Original Strategy to Avoid Cell Transplantation

“…Two behavioural tests were used after SCI to assess motor performances of rats: the Basso, Beattie and Bresnahan (BBB) open-field test [101] consisting of a 21 point rating scale, and the grid navigation test with a 5 point scale [102]. All rats were accustomed to both tests 1 week before SCI.…”

Effects of calcitriol on experimental spinal cord injury in rats

“…12 In brief, all rats (n = 6 per group) were tested in two positions (right side or left side up) on a testing apparatus (i.e., a board covered with a rubber mat containing horizontal ridges that were spaced 3 mm apart). For each position, the maximum angle at which a rat could maintain its position for 5 s without falling was recorded and averaged to obtain a single score for each rat.…”

Cell Transplantation for Spinal Cord Injury: A Systematic Review

“…By utilizing Ngn2 expressing ESC-derived NPCs, Perrin et al and Shapiro et al fully restored weight support and significantly improved functional motor recovery of rats after severe spinal cord compression injury. In addition, the expression of serotonin 5HT1A receptor, which is expressed in the raphespinal tract which plays a major role in locomotion and is particularly affected after SCI, was partially restored [48, 116]. In another report, Hatami et al injected human embryonic stem cell-derived NPCs (hESC-NPCs) with collagen scaffolds into hemisection rat model.…”