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Open Access Highly Accessed Research

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

Sebastiaan van Gorp12, Marjolein Leerink1, Osamu Kakinohana1, Oleksandr Platoshyn1, Camila Santucci1, Jan Galik34, Elbert A Joosten2, Marian Hruska-Plochan167, Danielle Goldberg1, Silvia Marsala1, Karl Johe5, Joseph D Ciacci18 and Martin Marsala139*

Author Affiliations

1 Neuroregeneration Laboratory, Department of Anesthesiology, University of California, San Diego, 9500 Gilman Drive, 92093, La Jolla, CA, USA

2 Department of Anesthesiology, School for Mental Health and Neuroscience, Maastricht University Medical Center, Universiteitssingel 40, 6229, ER Maastricht, The Netherlands

3 Institute of Neurobiology, Slovak Academy of Sciences, Soltesovej 9, 04001, Kosice, Slovakia

4 Institute of Biology and Ecology, Faculty of Science, Pavol Jozef Safarik University, Srobarova 2, 04154, Košice, Slovakia

5 Neuralstem, Inc, 9700 Great Seneca Hwy, Rockville, MD 20850, USA

6 Institute of Animal Physiology and Genetics, Czech Academy of Sciences, Rumburska 89, 277 21, Libechov, Czech Republic

7 Department of Cell Biology, Faculty of Science, Charles University in Prague, Vinicna 7, 128 00, Prague, Czech Republic

8 UCSD Division of Neurosurgery, University of California, San Diego, 9500 Gilman Drive, 92093, La Jolla, CA, USA

9 Sanford Consortium for Regenerative Medicine, 2880 Torrey Pines Scenic Drive, 92037, La Jolla, CA, USA

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Stem Cell Research & Therapy 2013, 4:57  doi:10.1186/scrt209

Published: 28 May 2013

Abstract

Introduction

Intraspinal 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.

Methods

Three-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.

Results

Intraspinal 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.

Conclusions

Peri-acute intraspinal grafting of HSSC can represent an effective therapy which ameliorates motor and sensory deficits after traumatic spinal cord injury.

Keywords:
Spinal cord injury; Human neural stem cells; Spinal grafting; Functional recovery; Rat