TOP ＞ Symposium

Symposium 15 Advancement of understanding of nerve repair mechanism：a common priciple of neuronal development and regeneration シンポジウム15 ここまで進んだ神経修復機構の理解：神経発生と神経再生の共通原理と将来展望 SY15-1 The biological systems that regulate restoration of the injured neuronal network in the central nervous system 中枢神経回路の修復を制御する生体システム Yamashita Toshihide（山下 俊英） Dept. of Mol. Neurosci., Grad. Sch. of Med., Osaka Univ Neurological disorders such as cerebrovascular disease, focal and central nervous system disorders from traumatic brain and spinal cord injury, higher brain dysfunction, and neuropathic pain, form their pathology and bring about spatiotemporal changes in the biological system which is made up not only of the nervous system but the immune system, the vascular system, and various organs. In this study, we analyze central neural circuit disorders and the subsequent restoration process from the viewpoint of the functional network of the biological system, and attempt to reveal in an integrated manner the control mechanism for the series of processes using the spatiotemporal dynamics of the biological system. The research particularly aims to uncover the control mechanism based on the linkage between the nervous system and each organ. We approach the process of central neural circuit disorders and functional recovery as the dynamics of the entire biological system and analyze the linkage between the nervous system and each system in an integrated manner to clarify the working principles of the living body with regard to central neural circuit disorders. SY15-2 Scaffolds for neuronal migration during brain development and regeneration 脳の発達・再生過程における新生ニューロンの移動の足場 Sawamoto Kazunobu（澤本 和延）1,2 1Dept. of Dev. & Regen. Biol., Nagoya City Univ. Grad. Sch. Med., Nagoya, Japan 2Div. of Neural Development & Regeneration, NIPS, Okazaki, Japan Immature neurons, referred to as neuroblasts, generated from neural stem cells in a neurogenic niche, the ventricular-subventricular zone (V-SVZ) of the walls of the lateral ventricles, migrate toward their destinations in the postnatal brain. After brain injuries, these neuroblasts migrate toward the injured area, where they differentiate into mature neurons. To move toward the lesion, neuroblasts form chain-like aggregates and migrate along blood vessels, which are thought to increase their migration efficiency. The neuroblast chain formation and blood vessel-guided migration critically depend on β1 integrin signaling. Moreover, artificial laminin-containing scaffolds promote neuroblast chain formation and migration toward the injured area. Radial glia are polarized embryonic neural stem cells, which guide newly generated neurons by providing their fibers as a migratory scaffold. Radial glial fibers are maintained for an extended period in the injured neonatal mouse brain and provide a scaffold on which V-SVZ-derived new neurons migrate toward the injured cerebral cortex. N-cadherin-mediated cell-cell contact promotes RhoA activation in the new neurons and maintains their directional saltatory movement along radial glial fibers. Inserting radial glial fiber-mimetic scaffold into the brain promotes new-neuron migration toward the lesion and facilitated neuronal regeneration and neurological recovery. These findings have revealed the functional significance of blood vessels and neonatal radial glia as scaffolds for neuronal regeneration after brain injury. We propose novel therapeutic strategies for repairing the injured brain using endogenous neurogenesis in the V-SVZ. SY15-3 Preservation of the injured site boosts up neural stem cell transplantation-mediated functional recovery after spinal cord injury 損傷部位保全により促進される移植神経幹細胞の脊髄損傷治療効果 Nakashima Kinichi（中島 欽一） Dept. Stem Cell Biol. Med., Grad. Sch Med. Sci., Kyushu Univ. Together with residual host neurons, transplanted neural stem cell (NSC)-derived neurons play a critical role in reconstructing disrupted neural circuits after spinal cord injury (SCI). Since a large number of tracts are disrupted and the majority of host neurons die around the lesion site as the damage spreads, minimizing this spreading and preserving the microenvironment around the lesion are important for attaining further improvements in reconstruction. High mobility group box-1 (HMGB1) is a damage-associated molecular pattern protein that triggers sterile inflammation after tissue injury. In the ischemic and injured brain, neutralization of HMGB1 with a specific antibody reportedly stabilizes the blood-brain barrier, suppresses inflammatory cytokine expression, and improves functional recovery. Using a SCI model mouse, we here developed a combinatorial treatment for SCI: administering anti-HMGB1 antibody prior to transplantation of NSCs derived from human induced pluripotent stem cells (hiPSC-NSCs) yielded a dramatic improvement in locomotion recovery after SCI. Even anti-HMGB1 antibody treatment alone alleviated blood-spinal cord barrier disruption and edema formation, and increased the number of neurites from spared axons and the survival of host neurons, resulting in functional recovery. However, this recovery was greatly enhanced by the subsequent hiPSC-NSC transplantation, reaching an extent that has never before been reported. We also found that this improved recovery was directly associated with connections established between surviving host neurons and transplant-derived neurons. Taken together, our results highlight combinatorial treatment with anti-HMGB1 antibody and hiPSC-NSC transplantation as a promising novel therapy for SCI. SY15-4 Application of an endogenous Nogo receptor antagonist LOTUS to regenerative medicine 内在性Nogo受容体アンタゴニストLOTUSの神経再生医療への適用 Takei Kohtaro（竹居 光太郎） Mol. Med. Biosci. Lab., Yokohama City Univ. Grad. Sch. Med. Life Sci., Yokohama, Japan Axonal regeneration in the adult mammalian central nervous system (CNS) is limited by the non-permissive environment, including axonal growth inhibitors such as the Nogo protein. Previously, we have identified lateral olfactory tract usher substance (LOTUS) as an endogenous antagonist for Nogo receptor-1 (NgR1). LOTUS consists of the membrane-bound form and the secreted soluble form. We found that both type of LOTUS interacts with NgR1 and blocks NgR1-mediated signaling, resulting in the suppression of growth cone collapse and neurite outgrowth inhibition induced by all five NgR1 ligands such as Nogo, MAG, OMgp, BLyS and cCSPGs. Therefore, LOTUS is expected to be a potent therapeutic agent for neuronal regeneration after injury in the CNS. We examined the role of LOTUS in promoting functional recovery and neural repair after spinal cord injury (SCI), as well as axonal regeneration after optic nerve crush and brain ischemia. Wild-type untreated mice show incomplete but substantial intrinsic motor recovery after SCI, whereas the genetic deletion of LOTUS delays and decreases the extent of motor recovery. The neuronal overexpression of LOTUS in transgenic mice promotes motor recovery after SCI and brain ischemia. Furthermore, the administration of purified recombinant LOTUS protein in injured site also promotes motor recovery after SCI. In addition, recombinant viral overexpression or administration of purified LOTUS protein enhances retinal ganglion cell axonal regeneration after optic nerve crush. These findings strongly suggest that LOTUS can be used for therapeutic natural agent in nerve repair and may have potential for the clinical treatment of humans with CNS axonal injury. I will discuss future perspective of therapeutic strategy using LOTUS.