| Co-Investigator(Kenkyū-buntansha) |
WATANABE Kota Keio University, School of Medicine, Assistant, 医学部, 助手 (60317170)
OKANO Hideyuki Keio University, School of Medicine, Professor, 医学部, 教授 (60160694)
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| Budget Amount *help |
¥3,200,000 (Direct Cost: ¥3,200,000)
Fiscal Year 2003: ¥1,500,000 (Direct Cost: ¥1,500,000)
Fiscal Year 2002: ¥1,700,000 (Direct Cost: ¥1,700,000)
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| Research Abstract |
Recently, we have shown that the transplantation of spinal cord-derived neural stem/progenitor cells (NSPCs) can contribute to the repair of injured spinal cord in adult rats, which may correspond to a behavioral recovery. To apply these results to clinical practice, a system for supplying human NSPCs on a large-scale must be established. However, human spinal cord-derived NSPCs are known to have a low proliferation rate, compared with forebrain derived NSPCs. This low proliferate potency limits the feasibility of large-scale spinal cord derived NSPC use. Thus, forebrain-derived NSPCs should be examined as an alternative to spinal cord-derived NSPCs for treatment of spinal cord injuries. In this study, we compared spinal cord-and forebrain-derived NSPCs transplanted into injured spinal cord with respect to their fates in vivo as well as the animals' functional recovery. Both spinal cord-and forebrain derived NSPCs promoted functional recovery in rats with spinal cord injuries. While bo
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th spinal cord-and forebrain-derived NSPCs survived, migrated, and differentiated into neurons, astrocytes and oligodendrocytes in response to the microenvironment within the injured spinal cord after transplantation, forebrain-derived NSPCs differentiated into more neurons and fewer oligodendrocytes, compared to spinal cord-derived NSPCs.
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. MR16-1 not only suppressed the astrocytic differentiation-promoting effect of IL-6 signaling in vitro but also 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. Less
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