Amelioration of motor/sensory dysfunction and spasticity in a rat model of acute lumbar spinal cord injury by human neural stem cell transplantation

Abstract

IntroductionIntraspinal grafting of human neural stem cells represents a promising approach to promote recovery of function after spinal trauma. Such a treatment may serve to: I) provide trophic support to improve survival of host neurons; II) improve the structural integrity of the spinal parenchyma by reducing syringomyelia and scarring in trauma-injured regions; and III) provide neuronal populations to potentially form relays with host axons, segmental interneurons, and/or α-motoneurons. Here we characterized the effect of intraspinal grafting of clinical grade human fetal spinal cord-derived neural stem cells (HSSC) on the recovery of neurological function in a rat model of acute lumbar (L3) compression injury.MethodsThree-month-old female Sprague–Dawley rats received L3 spinal compression injury. Three days post-injury, animals were randomized and received intraspinal injections of either HSSC, media-only, or no injections. All animals were immunosuppressed with tacrolimus, mycophenolate mofetil, and methylprednisolone acetate from the day of cell grafting and survived for eight weeks. Motor and sensory dysfunction were periodically assessed using open field locomotion scoring, thermal/tactile pain/escape thresholds and myogenic motor evoked potentials. The presence of spasticity was measured by gastrocnemius muscle resistance and electromyography response during computer-controlled ankle rotation. At the end-point, gait (CatWalk), ladder climbing, and single frame analyses were also assessed. Syrinx size, spinal cord dimensions, and extent of scarring were measured by magnetic resonance imaging. Differentiation and integration of grafted cells in the host tissue were validated with immunofluorescence staining using human-specific antibodies.ResultsIntraspinal grafting of HSSC led to a progressive and significant improvement in lower extremity paw placement, amelioration of spasticity, and normalization in thermal and tactile pain/escape thresholds at eight weeks post-grafting. No significant differences were detected in other CatWalk parameters, motor evoked potentials, open field locomotor (Basso, Beattie, and Bresnahan locomotion score (BBB)) score or ladder climbing test. Magnetic resonance imaging volume reconstruction and immunofluorescence analysis of grafted cell survival showed near complete injury-cavity-filling by grafted cells and development of putative GABA-ergic synapses between grafted and host neurons.ConclusionsPeri-acute intraspinal grafting of HSSC can represent an effective therapy which ameliorates motor and sensory deficits after traumatic spinal cord injury.

The influence of neurotransplantation with different allogenic tissues on the course of the spasticity and chronic pain syndrome after experimental spinal cord injury

“…492-497, 511, 514-519] при спінальній травмі залежить від реалізації компонентів запального процесу, характерного у тому числі для будь-якого нейроінженерного втручання трансплантаційного типу [26,27]. Попри цей оче-видний факт, вивчення впливу таких втручань при спінальній травмі на перебіг синдрому спастичності [28,29] та хронічного больового синдрому [30][31][32][33][34][35][36][37][38][39][40] становить міноритарну частку робіт, присвячених темі відновного лікування спінальної травми. Крім того, очевидним є факт обмеження сучасних нейроінженер-них втручань при спінальній травмі [41][42][43][44]; відсутній порівняльний аналіз їх ефективності на тлі тканинної нейротрансплантації, передусім тих її варіантів, що оперують найбільш місткими джерелами потенційних учасників нейропластичного процесу.…”

Cell Therapy of Stroke and Spinal Cord Injury Complications

“…На основании предклинических данных, опубликованных van Gorp и соавт [59], а так-же Lu и соавт [60], демонстрирующих положи-тельный эффект трансплантации НСК, выде-ленных из человеческого фетального спинного мозга и эмбриона человека, соответственно, для терапии ПСМТ, компания Neuralstem Inc. (Germantown, MD) начала в августе 2014 года I фазу клинических испытаний (по данным сайта clinicaltrials.gov). Это многоцентровое исследование, использующее трансплантацию стволовых клеток для терапии ПСМТ, являет-ся близким по технологии к тому, что проводи-ла ранее корпорация Geron (Menlo Park, CA).…”

Stem cells: A time to heal

“…Neuralstem's cells have already been tested in 18 patients with amyotrophic lateral sclerosis, a motor neuron disease better known as Lou Gehrig's disease, with no reported serious side effects. And a study published in May 2013 reports that these cells repopulate the cavity that forms in the wake of spinal injury in rats and restore some of the lost function, including sensory responses and movement 4 .…”