Neurons derived from transplanted neural stem cells restore disrupted neuronal circuitry in a mouse model of spinal cord injury.
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.
Abematsu
Masahiko
M
Laboratory of Molecular Neuroscience, Graduate School of Biological Sciences, Nara Institute of Science and Technology, Ikoma, Japan.
Tsujimura
Keita
K
Yamano
Mariko
M
Saito
Michiko
M
Kohno
Kenji
K
Kohyama
Jun
J
Namihira
Masakazu
M
Komiya
Setsuro
S
Nakashima
Kinichi
K
D000818:Animals; D002454:Cell Differentiation / Q000502:physiology; D056572:Histone Deacetylase Inhibitors; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D039902:Multipotent Stem Cells / Q000637:transplantation; D009434:Neural Pathways / Q000502:physiology / Q000503:physiopathology*; D058953:Neural Stem Cells / Q000637:transplantation*; D009457:Neuroglia / Q000637:transplantation; D009474:Neurons / Q000166:cytology* / Q000637:transplantation*; D011712:Pyramidal Tracts / Q000503:physiopathology; D020127:Recovery of Function; D013119:Spinal Cord Injuries / Q000503:physiopathology / Q000601:surgery / Q000628:therapy*
D056572:Histone Deacetylase Inhibitors