Yuji Mikami

Blockade of interleukin-6 receptor suppresses reactive astrogliosis and ameliorates functional recovery in experimental spinal cord injury.

Endogenous neural stem/progenitor cells (NSPCs) have recently been shown to differentiate exclusively into astrocytes, the cells that are involved in glial scar formation after spinal cord injury (SCI). The microenvironment of the spinal cord, especially the inflammatory cytokines that dramatically increase in the acute phase at the injury site, is considered to be an important cause of inhibitory mechanism of neuronal differentiation following SCI. Interleukin‐6 (IL‐6), which has been demonstrated to induce NSPCs to undergo astrocytic differentiation selectively through the JAK/STAT pathway in vitro, has also been demonstrated to play a critical role as a proinflammatory cytokine and to be associated with secondary tissue damage in SCI. In this study, we assessed the efficacy of rat anti‐mouse IL‐6 receptor monoclonal antibody (MR16‐1) in the treatment of acute SCI in mice. Immediately after contusive SCI with a modified NYU impactor, mice were intraperitoneally injected with a single dose of MR16‐1 (100 μg/g body weight), the lesions were assessed histologically, and the functional recovery was evaluated. MR16‐1 not only suppressed the astrocytic diffentiation‐promoting effect of IL‐6 signaling in vitro but inhibited the development of astrogliosis after SCI in vivo. MR16‐1 also decreased the number of invading inflammatory cells and the severity of connective tissue scar formation. In addition, we observed significant functional recovery in the mice treated with MR16‐1 compared with control mice. These findings suggest that neutralization of IL‐6 signaling in the acute phase of SCI represents an attractive option for the treatment of SCI.

Implantation of dendritic cells in injured adult spinal cord results in activation of endogenous neural stem/progenitor cells leading to de novo neurogenesis and functional recovery

We report a treatment for spinal cord injury involving implantation of dendritic cells (DCs), which act as antigen‐presenting cells in the immune system. The novel mechanisms underlying this treatment produce functional recovery. Among the immune cells tested, DCs showed the strongest activity inducing proliferation and survival of neural stem/progenitor cells (NSPCs) in vitro. Furthermore, in DC‐implanted adult mice, endogenous NSPCs in the injured spinal cord were activated for mitotic de novo neurogenesis. These DCs produced neurotrophin‐3 and activated endogenous microglia in the injured spinal cord. Behavioral analysis revealed the locomotor functions of DC‐implanted mice to have recovered significantly as compared to those of control mice. Our results suggest that DC‐implantation exerts trophic effects, including activation of endogenous NSPCs, leading to repair of the injured adult spinal cord.