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It is thought that spinal cord injury triggers scar formation with little axon regeneration in mammals 1 – 4 . Here we report that in neonatal mice, a crush injury to the spinal cord leads to a scar-free healing that permits the growth of long projecting axons through the lesion. Depletion of microglia in neonates disrupts such healing and stalls axon regrowth, suggesting a critical role for microglia in orchestrating the injury response. Using single cell RNA-sequencing and functional analyses, we discovered that neonatal microglia undergo a transient activation and play at least two critical roles in scar-free healing. First, they transiently secrete fibronectin and its binding proteins, to form extracellular matrix bridges that ligate the severed ends. Second, neonatal, but not adult, microglia express a number of extracellular and intracellular peptidase inhibitors, along with other molecules involved in inflammatory resolution. Strikingly, upon transplantation into adult spinal cord lesions, both adult microglia treated with peptidases inhibitors and neonatal microglia significantly improve healing and axon regrowth. Together, our results reveal the cellular and molecular basis underlying the nearly complete recovery after spinal cord injury in neonatal mice, pointing to potential strategies to facilitate scar-free healing in the adult mammalian nervous system.

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