Spinal cord injury in mammals is thought to trigger scar formation with little regeneration of axons 1 – 4 . Here we show that a crush injury to the spinal cord in neonatal mice leads to scar-free healing that permits the growth of long projecting axons through the lesion. Depletion of microglia in neonatal mice disrupts this healing process and stalls the regrowth of axons, suggesting that microglia are critical for orchestrating the injury response. Using single-cell RNA sequencing and functional analyses, we find that neonatal microglia are transiently activated and have at least two key roles in scar-free healing. First, they transiently secrete fibronectin and its binding proteins to form bridges of extracellular matrix that ligate the severed ends of the spinal cord. Second, neonatal—but not adult—microglia express several extracellular and intracellular peptidase inhibitors, as well as other molecules that are involved in resolving inflammation. We transplanted either neonatal microglia or adult microglia treated with peptidase inhibitors into spinal cord lesions of adult mice, and found that both types of microglia significantly improved healing and axon regrowth. Together, our results reveal the cellular and molecular basis of the nearly complete recovery of neonatal mice after spinal cord injury, and suggest strategies that could be used to facilitate scar-free healing in the adult mammalian nervous system. In neonatal mice, scar-free healing after spinal cord injury is organized by microglia, and transplantation of neonatal microglia or peptidase-inhibitor-treated adult microglia into adult mice after injury improves healing and axon regrowth.

中文翻译：

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新生小鼠小胶质细胞组织的无疤痕脊髓修复

哺乳动物的脊髓损伤被认为会引发疤痕形成，而轴突 1 – 4 几乎没有再生。在这里，我们展示了新生小鼠脊髓挤压伤导致无疤痕愈合，允许长突出的轴突通过病变生长。新生小鼠中小胶质细胞的消耗会破坏这种愈合过程并阻止轴突的再生，这表明小胶质细胞对于协调损伤反应至关重要。使用单细胞 RNA 测序和功能分析，我们发现新生儿小胶质细胞被瞬时激活，并且在无疤痕愈合中至少有两个关键作用。首先，它们瞬时分泌纤连蛋白及其结合蛋白，形成细胞外基质桥，连接脊髓的切断末端。第二，新生儿——但不是成人——小胶质细胞表达几种细胞外和细胞内肽酶抑制剂，以及其他参与解决炎症的分子。我们将用肽酶抑制剂治疗的新生小胶质细胞或成年小胶质细胞移植到成年小鼠的脊髓损伤中，发现这两种类型的小胶质细胞显着改善了愈合和轴突再生。总之，我们的结果揭示了脊髓损伤后新生小鼠几乎完全恢复的细胞和分子基础，并提出了可用于促进成年哺乳动物神经系统无疤痕愈合的策略。在新生小鼠中，脊髓损伤后的无疤痕愈合是由小胶质细胞组织的，