Glial cell responses promote spinal cord repair in zebrafish

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.