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Arthritis Research & Therapy

Open Access

Reconstruction of injured spinal cord by epigenetic regulation of transplanted neural stem cells

  • Masahiko Abematsu1, 2, 3,
  • Keita Tsujimura3,
  • Mariko Yamano5,
  • Michiko Saito4,
  • Kenji Kohno4,
  • Takao Setoguchi1, 2,
  • Kazunori Yone1,
  • Kinichi Nakashima3 and
  • Setsuro Komiya1, 2
Arthritis Research & Therapy201214(Suppl 1):P1

Published: 29 February 2012


Spinal Cord InjuryValproic AcidNeural Stem CellInjured Spinal CordAdult Central Nervous System


Neural stem cells (NSCs) possess the ability to self-renew and to differentiate into the three major cell types found in the central nervous system (CNS). Recent studies have shown that epigenetic gene regulation events such as DNA methylation and histone modification play important roles in regulating NSC fate specification. In this context, we have previously shown that the histone deacetylase inhibitor valproic acid (VPA) enhances neuronal differentiation of NSCs. Perhaps because these patterns of NSC differentiation are exquisitely controlled during normal embryonic development, restoration of damaged neural networks in the injured adult CNS is severely limited. Here, using a mouse model of spinal cord injury(SCI), we examined the effectiveness of NSC transplantation and differentiation control by VPA administration.

Materials and methods

NSCs were transplanted into the SCI epicenter 7 days after injury. Non-transplanted control and transplanted mice were then intraperitoneally administered VPA or saline daily, for 7 days, whereafter we monitored their hindlimb motor function using the open field locomotor scale for 6 weeks. We next analyzed the migration, morphology, neuronal marker expression and viability of these cells after co-administration with VPA. We examined extensively the roles of the neurons responsible for reconstruction of broken neuronal networks using two neuronal tracers, immunoelectron microscopy, and two cell-ablation methods.


We show that transplanting NSCs and administering VPA enhances the functional recovery of their hindlimbs. Neuronal differentiation of transplanted NSCs was promoted in VPA-treated mice. Anterograde corticospinal tract tracing revealed that transplant-derived neurons partially reconstructed the broken neuronal circuits, most likely in a 'relay' manner. Ablation of the transplanted cells abolished the recovery of hindlimb motor function, indicating that transplanted cells contributed directly to the improvement of motor function.


These data raise the possibility that epigenetic regulation in transplanted neural stem cells can be exploited to provide treatment for SCI.

Authors’ Affiliations

Department of Orthopaedic Surgery, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan
The Near-Future Locomotor Organ Medicine Creation Course (Kusunoki Kai), Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan
Laboratory of Molecular Neuroscience, Graduate School of Biological Sciences, Nara Institute of Science and Technology, Ikoma, Japan
Laboratory of Molecular and Cell Genetics, Graduate School of Biological Sciences, Nara Institute of Science and Technology, Ikoma, Japan
Department of Comprehensive Rehabilitation, Osaka Prefecture University, Habikino, Japan


© Abematsu et al.; licensee BioMed Central Ltd. 2012

This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.