Placental Mesenchymal Stromal Cells Improve Forelimb Motor Function in a Rodent Cervical Spinal Cord Contusion Model
Vanover M, Pivetti C, Kumar P, Chung K, Galganski L, Farmer D, Wang A
University of California, Davis, Sacramento, California, USA
Objective: Placental mesenchymal stromal cells (PMSCs) improve motor function following in utero application in an ovine model of spina bifida, a congenital form of spinal cord injury . Spinal cord injury in spina bifida is due to a combination of exposure to toxic amniotic fluid and direct intrauterine trauma to the exposed spinal cord . In addition to improved hindlimb function, neuronal preservation within the spinal cord of animals treated with PMSCs suggests paracrine secretion of immunomodulatory and neurotrophic factors as the primary mechanism of action . The objective of this study was to determine if similar functional improvement can be seen after treatment of acquired cervical spinal cord injury in a rodent model.
Design/Method: Adult Sprague-Dawley rats underwent a unilateral cervical spinal cord contusion injury (SCI) using the NYU/MASCIS III Impactor . Briefly, the cervical vertebrae were exposed and a C5 hemilaminectomy performed. A 10-gm impactor rod with a 2.0 mm diameter tip was dropped from a height of 12.5 mm onto the right half of the exposed spinal cord. Injury was confirmed by the presence of visible ecchymosis and examination of the computer-generated impact curve. Three days after injury, the cervical spine was re-exposed and 5x105 PMSCs in 5 μL PBS was injected intrathecally using a glass micropipette. Control animals underwent injection of 5 μL PBS alone. All rats received 100 μg/mL cyclosporine-treated drinking water starting the day of the SCI and continuing until study end-point. Functional tests were performed pre-operatively and for 8 weeks after treatment. Distal forelimb function was evaluated using the validated Irvine, Beattie, Bresnahan (IBB) Forelimb Recovery Scale (range 0-9, 0 = complete paralysis, 9 = extensive forelimb use) . Two-way ANOVA was used to compare treatment groups.
Results: Seven rats underwent a unilateral cervical spinal cord contusion injury. Five rats were randomized into PMSC treatment group and two into PBS only treatment group. Initial post-operative functional tests were consistent with a moderate unilateral cervical cord contusion injury for all animals (IBB 0-1). Over 8 weeks post-treatment, significant improvement in ipsilateral forelimb function was seen in animals treated with PMSCs compared to those treated with PBS alone (p<0.0001).
Conclusion: Treatment of unilateral cervical spinal cord contusion injury with placental mesenchymal stromal cells during the acute post-injury period resulted in significant improvement in functional recovery of the affected forelimb in this pilot study. Given these promising results, further studies are planned to determine the exact mechanism of action and optimal dosing prior to translation to human trials.
Support: This work was supported in part by the California Institute for Regenerative Medicine pre-clinical development award PC1-08103, NIH grant #1R01NS100761-01A1, Shriners Hospital for Children research grant, and March of Dimes Foundation grant #5FY1682.
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