Grafted astroglia/astrocytes exhibit neuroprotective effects and improve functional recovery after injury to the central nervous system. This study sought to elucidate their ability to repair spinal cord lesions and the underlying mechanisms./nMethods: Complete spinal transection, transplantation of astroglia generated from human ESC-derived neural progenitor cells (NPC-Astros) or Olig2-GFP knock-in progenitors (Olig2PC-Astros), and immunostaining were used to determine the survival of astroglia. CUBIC tissue-clearing, immunostaining, electromyography, and functional tests such as the Basso Mouse Scale score and gait analysis were applied to analyze the recovery of the lesion area, axon regeneration, synapse formation, and motor function. Sholl analysis, immunostaining, depletion of anti-inflammatory microglia, and western blotting were employed to explore the cellular and molecular mechanisms underlying spinal cord repair./nResults: Grafted NPC- or Olig2PC-Astros survived in the lesion area and assisted wound healing by reducing scar formation and promoting regrowth of descending serotonergic axons and synapse reformation beyond the lesion area. These positive effects resulted in increased Basso Mouse Scale scores and improved hindlimb function as determined by electromyography and gait analysis. Activated microglia in the lesion area were shifted towards an anti-inflammatory phenotype after transplantation of NPC- or Olig2PC-Astros, and depletion of anti-inflammatory microglia reversed the observed improvements in the lesion area and axon regeneration. Transplantation of NPC- or Olig2PC-Astros elevated the expression of interleukin-4 and promoted the phenotypic shift of microglial via interleukin-4 downstream signaling./nConclusion: Our findings indicate that grafted human ESC-derived NPC- or Olig2PC-Astros promote recovery of the injured spinal cord by shifting microglia towards an anti-inflammatory state in the lesion area and activating interleukin-4 signaling.

中文翻译：

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移植的人 ESC 衍生星形胶质细胞通过激活病变区域的宿主抗炎小胶质细胞修复脊髓损伤

移植的星形胶质细胞/星形胶质细胞表现出神经保护作用并改善中枢神经系统损伤后的功能恢复。本研究旨在阐明它们修复脊髓损伤的能力及其潜在机制。/n 方法：完整的脊髓横断、移植由人类 ESC 衍生的神经祖细胞 (NPC-Astros) 或 Olig2-GFP 敲入祖细胞 (Olig2PC-Astros) 产生的星形胶质细胞和免疫染色用于确定星形胶质细胞的存活率。应用 CUBIC 组织清除、免疫染色、肌电图和功能测试，例如 Basso Mouse Scale 评分和步态分析来分析病变区域的恢复、轴突再生、突触形成和运动功能。采用 Sholl 分析、免疫染色、消炎小胶质细胞和蛋白质印迹来探索脊髓修复的细胞和分子机制。/n结果：移植的 NPC 或 Olig2PC-Astros 在病变区域存活并通过减少疤痕形成和促进下行 5-羟色胺能轴突的再生和病变区域以外的突触重组来帮助伤口愈合。通过肌电图和步态分析，这些积极影响导致 Basso Mouse Scale 评分增加和后肢功能改善。在移植 NPC-或 Olig2PC-Astros 后，病变区域中活化的小胶质细胞转变为抗炎表型，抗炎小胶质细胞的消耗逆转了观察到的病变区域和轴突再生的改善。NPC-或Olig2PC-Astros的移植提高了IL-4的表达，并通过IL-4下游信号促进了小胶质细胞的表型转变。/n结论：我们的研究结果表明，移植的人类 ESC 衍生的 NPC 或 Olig2PC-Astros 通过将小胶质细胞转移到病变区域的抗炎状态并激活白细胞介素 4 信号传导来促进受损脊髓的恢复。