scRNAseq analysis of mouse L4 whole dorsal root ganglions with and without sciatic nerve crush injury

Peripheral sensory neurons with cell body in dorsal root ganglia (DRG) switch to a regenerative state after nerve injury to enable axon regeneration and functional recovery. Studies of nerve injury responses in sensory neurons have revealed signaling and transcriptional mechanisms that increase their intrinsic regenerative capacity. However, the extent to which satellite glial cells (SGC), which completely surround the neuronal soma contribute to these responses remains unexplored. Using single cell RNA-seq, we defined the transcriptional profile of SGC in naïve and injured conditions and identified Fabp7, also known as BLBP, as a novel marker of SGC. We report that nerve injury elicits gene expression changes in SGC, which are mostly related to lipid metabolism, specifically fatty acid synthesis and the peroxisome proliferator-activated receptor (PPAR) signaling. Conditional deletion of Fatty acid synthase (Fasn), the key enzyme in de novo fatty acid synthesis, specifically in SGC, impairs axon regeneration. Treatment with fenofibrate, a PPARa agonist, rescues the impaired regeneration, suggesting that PPRAa, which belongs to a family of lipid regulated transcription factors, functions downstream of fatty acid synthesis in SGC to promote axon regeneration. These results unravel fatty acid synthesis in SGC as a fundamental novel mechanism mediating axon regeneration in mature peripheral nerves.

胞体位于背根神经节（dorsal root ganglia, DRG）的外周感觉神经元，在神经损伤后会切换至再生状态，以支持轴突再生与功能恢复。针对感觉神经元神经损伤应答的研究，已揭示了可提升其内在再生能力的信号转导与转录调控机制。然而，完全包裹神经元胞体的卫星胶质细胞（satellite glial cells, SGC）在这些应答中所发挥的作用程度仍未得到探索。本研究借助单细胞RNA测序（single cell RNA-seq），明确了正常未损伤与损伤状态下SGC的转录组特征，并鉴定出脂肪酸结合蛋白7（Fabp7，又称BLBP）作为SGC的新型标志物。我们发现，神经损伤会引发SGC内的基因表达变化，这些变化主要与脂质代谢相关，具体涉及脂肪酸合成以及过氧化物酶体增殖物激活受体（peroxisome proliferator-activated receptor, PPAR）信号通路。在SGC中条件性敲除从头脂肪酸合成的关键酶——脂肪酸合酶（Fatty acid synthase, Fasn），会损害轴突再生。使用PPARα激动剂非诺贝特（fenofibrate）进行处理，可挽救这一受损的再生能力，这表明属于脂质调控转录因子家族的PPARα，在SGC中位于脂肪酸合成的下游，进而促进轴突再生。本研究结果揭示，SGC内的脂肪酸合成是介导成熟外周神经轴突再生的全新核心机制。