Glial cell responses promote spinal cord repair in zebrafish

摘要 每年约有18，000名美国人遭受新的脊髓损伤（SCI）。原发性和继发性损害 脊髓损伤引起的永久性损害感觉和运动功能，需要长期治疗， 康复和心理干预。因此，开发治疗或逆转SCI的疗法是一项紧迫的任务。 再生医学的需要。与哺乳动物不同的是，硬骨鱼可以自然地再生功能性神经组织。 并在脊髓完全横断后逆转瘫痪。尽管斑马鱼的先天脊髓修复 几十年来，神经胶质细胞对这种提高的再生能力的贡献是巨大的， 替补演员脊髓损伤后，成年斑马鱼启动了一个神经胶质桥，重新连接切断的脊髓， 支持功能性神经修复前再生胶质桥接区分斑马鱼脊髓和 发生而没有由哺乳动物脊髓引起的反应性神经胶质增生的有害结果。我们提出 斑马鱼的神经胶质组织了一系列短暂的，促进再生的反应，使脊髓修复。在 在这个提议中，我们将1）确定启动胶质桥接的早期损伤反应，2）识别胶质桥接 斑马鱼桥接神经胶质细胞特异性的机制和哺乳动物神经胶质细胞中缺乏的机制，以及3）揭示细胞的 以及再生完成后指导神经胶质桥解体的分子机制。本研究将 在斑马鱼脊髓再生过程中提供神经胶质细胞生物学的机制理解，并将指导 操纵神经胶质细胞以促进哺乳动物脊髓修复的方法。

ABSTRACT Around 18,000 Americans suffer new spinal cord injuries (SCI) each year. Primary and secondary damages caused by SCI permanently impair sensory and motor functions, which require long-term therapeutic, rehabilitative, and psychological interventions. Thus, developing therapies to treat or reverse SCI is a pressing need in regenerative medicine. In contrast to mammals, teleost fish naturally regenerate functional neural tissue and reverse paralysis after complete spinal cord transection. Although innate spinal cord repair in zebrafish has fascinated scientists for decades, the contribution of glial cells to this elevated regenerative capacity is vastly understudied. Following SCI, adult zebrafish initiate a glial bridge that reconnects the severed spinal cord and supports functional neural repair. Pro-regenerative glial bridging distinguishes the zebrafish spinal cord and occurs without the detrimental outcomes of reactive gliosis elicited by the mammalian spinal cord. We propose that zebrafish glia orchestrate a series of transient, pro-regenerative responses that enable spinal cord repair. In this proposal, we will 1) determine the early injury responses that initiate glial bridging, 2) identify glial bridging mechanisms that are specific to zebrafish bridging glia and absent in mammalian glia, and 3) uncover the cellular and molecular mechanisms that direct glial bridge disassembly after regeneration is complete. This study will provide a mechanistic understanding of glial cell biology during zebrafish spinal cord regeneration, and will guide approaches for manipulating glial cells to promote spinal cord repair in mammals.