Neurons derived from transplanted neural stem cells restore disrupted neuronal circuitry in a mouse model of spinal cord injury
Masahiko Abematsu, … , Setsuro Komiya, Kinichi Nakashima
Masahiko Abematsu, … , Setsuro Komiya, Kinichi Nakashima
Published August 16, 2010
Citation Information: J Clin Invest. 2010;120(9):3255-3266. https://doi.org/10.1172/JCI42957.
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Research Article

Neurons derived from transplanted neural stem cells restore disrupted neuronal circuitry in a mouse model of spinal cord injury

Abstract

The body’s capacity to restore damaged neural networks in the injured CNS is severely limited. Although various treatment regimens can partially alleviate spinal cord injury (SCI), the mechanisms responsible for symptomatic improvement remain elusive. Here, using a mouse model of SCI, we have shown that transplantation of neural stem cells (NSCs) together with administration of valproic acid (VPA), a known antiepileptic and histone deacetylase inhibitor, dramatically enhanced the restoration of hind limb function. VPA treatment promoted the differentiation of transplanted NSCs into neurons rather than glial cells. Transsynaptic anterograde corticospinal tract tracing revealed that transplant-derived neurons reconstructed broken neuronal circuits, and electron microscopic analysis revealed that the transplant-derived neurons both received and sent synaptic connections to endogenous neurons. Ablation of the transplanted cells abolished the recovery of hind limb motor function, confirming that NSC transplantation directly contributed to restored motor function. These findings raise the possibility that epigenetic status in transplanted NSCs can be manipulated to provide effective treatment for SCI.

Authors

Masahiko Abematsu, Keita Tsujimura, Mariko Yamano, Michiko Saito, Kenji Kohno, Jun Kohyama, Masakazu Namihira, Setsuro Komiya, Kinichi Nakashima

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Figure 7

Diagrammatic summary of destruction and reconstruction of neural circuits in the injured spinal cord.

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Diagrammatic summary of destruction and reconstruction of neural circuit...
(A) In the acute phase of SCI, CST fibers are disrupted and hind limb movement is completely lost. (B) In the chronic phase, WGA transport through the lesion site to the caudal area is negligible, probably because very few CST fibers are restored. (D) When NSCs were transplanted to the injured spinal cord, almost all of them differentiated into astrocytes, with the result that very little restoration of the injured CST occurred. (C) Following VPA administration, neuronal differentiation of transplanted NSCs was greatly enhanced and dramatic functional recovery could be observed. WGA is conveyed through the lesion site to the caudal area via transplant-derived neurons. (E) Ablation of transplant-derived cells with DT nullified hind limb functional recovery, suggesting that the transplanted cells contribute directly to the functional recovery in hind limbs. (F) Ablation of residual local neurons in the lesion site by NMDA led to a complete impairment of hind limb movement, suggesting that residual local endogenous neurons also play an important role in the improvement of hind limb motor function.