Localized EMT reprograms glial progenitors to promote spinal cord repair

Anti-regenerative scarring obstructs spinal cord repair in mammals and presents a major hurdle for regenerative medicine. In contrast, adult zebrafish possess specialized glial cells that spontaneously repair spinal cord injuries by forming a pro-regenerative bridge across the severed tissue. To identify the mechanisms that regulate differential regenerative capacity between mammals and zebrafish, we first defined the molecular identity of zebrafish bridging glia and then performed cross-species comparisons with mammalian glia. Our transcriptomics show that pro-regenerative zebrafish glia activate an epithelial-to-mesenchymal transition (EMT) gene program and that EMT gene expression is a major factor distinguishing mammalian and zebrafish glia. Functionally, we found that localized niches of glial progenitors undergo EMT after spinal cord injury in zebrafish and, using large-scale CRISPR-Cas9 mutagenesis, we identified the gene regulatory network that activates EMT and drives functional regeneration. Thus, non-regenerative mammalian glia lack an essential EMT-driving gene regulatory network that reprograms pro-regenerative zebrafish glia after injury. [Display omitted] •Bulk and single cell transcriptomes of regenerative zebrafish glia were generated•Pathways that distinguish regenerative zebrafish glia from mammalian glia were defined•An injury-induced EMT transcriptional module localizes to zebrafish glial progenitors•EMT transcription factors direct mesenchymal fate and regenerative bridging in zebrafish Shaw et al. defined the molecular identity of regenerative zebrafish glia and performed cross-species comparisons with mammalian glia. They found that EMT localizes to zebrafish glial progenitors and distinguishes mammalian and zebrafish glia. They uncovered evidence that an EMT transcriptional module reprograms glial progenitors and promotes spinal cord repair in zebrafish.