Editors' ChoiceNeuroscience

Bridging the Gap in Spinal Cord Injury

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Science Translational Medicine  06 Oct 2010:
Vol. 2, Issue 52, pp. 52ec156
DOI: 10.1126/scitranslmed.3001753

Spinal cord injury (SCI) can result in paralysis with devastating physical and emotional consequences. Unfortunately, there are no treatments available to reverse damage to the spinal cord, and the body itself has limited capacity to regenerate the nervous system. Neural stem cells (NSCs) differentiate into multiple cell types, including neurons and glial cells. Upon transplantation into spinal cord lesions, NSCs have been reported to partially restore motor function in rodents. However, the effectiveness of this strategy is limited because the inflammatory milieu at the injury site induces NSCs to differentiate into glial cells instead of neurons. Abematsu et al. now overcome this problem by transplanting mouse NSCs together with valproic acid into spinal cord lesions in mice. This clinically approved drug promotes the differentiation of NSCs into neurons and not glial cells, resulting in partial repair of the lesions and improved motor function by the injured animals. This study shows that valproic acid may improve stem cell–based therapy and brings this approach a small step closer to clinical application.

Valproic acid, which is already clinically used to treat epilepsy, is a histone deacetylase inhibitor that regulates gene expression by altering the accessibility of chromatin around genes. The authors first demonstrated that valproic acid, when administered with NSCs into spinal cord lesions in mice, coaxed the NSCs to become neurons, not glial cells. They then showed, using a tracer that is transported along axons, that the neurons derived from NSCs were connected with neural circuits both above and below the injury site. Furthermore, electron microscopy revealed that the NSC-derived neurons made synaptic connections with existing neurons in the spinal cord. Next, the authors demonstrated that NSCs together with valproic acid, but not either treatment alone, resulted in improved hind-limb function and mobility in mice with spinal cord injury. Intriguingly, they found that the improvements in motor function were the result of both the NSC-derived neurons and endogenous neurons, working together. These encouraging findings demonstrate how manipulating the epigenetic status of NSCs with valproic acid during transplant boosts neuron production and spinal cord repair, resulting in improved motor function. This approach may improve the effectiveness of NSC-based therapies and may be applicable to other cell-based therapies as well.

M. Abematsu et al., Neurons derived from transplanted neural stem cells restore disrupted neuronal circuitry in a mouse model of spinal cord injury. J. Clin. Invest. 120, 3255–3266 (2010). [Full Text]

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