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.

Spinal cord injury (SCI) usually results in a large range of sensorimotor and autonomic nerve injury and remains a serious public health problem worldwide. SCI affects approximately 273 000 people in the United States, and there are some 12 000 new cases each year. 1-3 Therefore, SCI brings severe economy burdens and psychological pressure to patients. However, there are currently no effective therapies for SCI clinically, and an effective treatment is awaited. 4-6 This is due mainly to the molecular mechanisms of SCI remain elusive. The pathological process of SCI is known as a complex process, which can be classified into two phases: Primary injury is the direct mechanical damage of spinal cord tissue and includes demyelination and necrosis of neurons and axons; and the secondary injury is composed of a variety of pathophysiologic mechanisms, including local haemorrhage, ischaemia, oedema, ionic imbalance, free radical stress and inflammatory responses. 7,8 This complex pathological process of SCI may explain the difficulty in finding a suitable and effective therapy. Therefore, understanding the molecular mechanisms of SCI is critical for the development of therapeutic strategies. Cell death is known as the final stage of cells and it can be resulted from cytotoxicity from exogenous or endogenous substances. 9 In 1842, cell death was first posed by Carl Vogt, and lots of molecules are considered to be involved in this irreversible process to support the maintenance of cellular homeostasis. 10 Cell death was initially divided into two types, necrosis and apoptosis. 11 Necrosis is considered as a passive and accidental cell death, which can be resulted from environmental perturbations and the large amounts

This review is helpful for understanding the underlying mechanisms of SCI and the potential clinical value of miRNAs. miRNAs have the potential to be attractive tools and targets for novel diagnostic and therapeutic approaches of SCI.