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)。原发和继发损害 脊髓损伤会永久性地损害感觉和运动功能，这需要长期的治疗， 康复和心理干预。因此，开发治疗或逆转脊髓损伤的疗法是当务之急。 需要再生医学。与哺乳动物不同的是，硬骨鱼自然会再生功能神经组织 和完全脊髓横断术后的反向瘫痪。尽管斑马鱼天生的脊髓修复能力 几十年来，让科学家们着迷的是，神经胶质细胞对提高再生能力的贡献是巨大的 未得到充分研究。脊髓损伤后，成年斑马鱼启动神经胶质桥，重新连接切断的脊髓和 支持功能性神经修复。促进再生的胶质细胞桥接区分斑马鱼脊髓和 发生时没有哺乳动物脊髓引起的反应性胶质细胞增生症的有害后果。我们建议 斑马鱼神经胶质细胞协调一系列短暂的、促进再生的反应，使脊髓修复成为可能。在……里面 在这个提议中，我们将1)确定启动神经胶质细胞桥接的早期损伤反应，2)识别神经胶质细胞桥接 斑马鱼特有的连接神经胶质细胞的机制，而哺乳动物神经胶质细胞中没有这种机制，以及3)揭示了细胞 以及在再生完成后指导神经胶质桥拆解的分子机制。这项研究将 提供斑马鱼脊髓再生过程中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.