【科技前瞻】Cell Death Dis：神经干细胞源外泌体通过激活自噬缓解神经炎症

生物_医药_科研 2019-05-29

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脊髓损伤（spinal cord injury，SCI）可引起严重的不可逆运动功能障碍甚至死亡，而神经干细胞（neural stem cell，NSC）移植可促进脊髓损伤后的功能恢复，并通过释放旁分泌因子促进组织再生，目前NSC衍生的细胞外囊泡在脊髓损伤治疗中的应用还未有报道。近日，来自南京医科大学第一附属医院的研究人员发现神经干细胞分泌的小细胞外囊泡通过激活自噬发挥脊髓损伤后的细胞修复活性，相关研究结果发表在Cell Death and Disease杂志上。

脊髓损伤的严重程度取决于最初的创伤程度，脊髓损伤破坏神经元或切断轴突，并且由于炎症引起延迟性继发性损伤，可能导致水肿、神经细胞凋亡、空洞化和反应性神经胶质增生。研究表明，NSC移植具有独特的神经保护功能，可促进急性脊髓损伤后的功能恢复，但将干细胞直接移植到靶组织中仍然具有挑战性。例如，移植的干细胞由于缺血而导致存活率较低，还可能存在细胞去分化、免疫排斥等问题，限制了直接NSC移植治疗SCI的临床应用。在这项新的研究里，研究人员首次表明，NSC源小细胞外囊泡（NSC-derived small extracellular vesicles，NSC-sEVs）能够通过激活自噬减少神经细胞凋亡、抑制神经炎症和促进脊髓损伤模型大鼠的功能恢复。研究结果显示，NSC-sEVs可以显著降低SCI的程度、改善功能恢复、并减少大鼠的神经细胞凋亡、小胶质细胞激活和神经炎症。此外，NSC-sEVs可通过诱导自噬来调节细胞凋亡和炎症过程。具体地，NSC-sEVs增加了自噬标记蛋白LC3B和beclin-1的表达，并促进自噬体形成。NSC-sEV处理后，SCI区域显著减少，促凋亡蛋白Bax、caspase-3和促炎细胞因子TNF-α、IL-1β和IL-6的表达水平均显著降低，而抗凋亡蛋白Bcl-2的表达水平上调。然而，在自噬抑制剂3MA作用下，NSC-sEVs对细胞凋亡和神经炎症的这些抑制作用被显著逆转。这项研究结果表明，NSC-sEVs有可能通过促进自噬介导了早期SCI的功能恢复，是有潜力的SCI治疗手段。

推荐阅读原文：

Neural stem cell-derived small extracellular vesicles attenuate apoptosis and neuroinflammation after traumatic spinal cord injury by activating autophagy.

Spinal cord injury (SCI) can cause severe irreversible motor dysfunction and even death. Neural stem cell (NSC) transplantation can promote functional recovery after acute SCI in experimental animals, but numerous issues, including low-transplanted cell survival rate, cell de-differentiation, and tumor formation need to be resolved before routine clinical application is feasible. Recent studies have shown that transplanted stem cells facilitate regeneration through release of paracrine factors. Small extracellular vesicles (sEVs), the smallest known membrane-bound nanovesicles, are involved in complex intercellular communication systems and are an important vehicle for paracrine delivery of therapeutic agents. However, the application of NSC-derived small extracellular vesicles (NSC-sEVs) to SCI treatment has not been reported. We demonstrate that NSC-sEVs can significantly reduce the extent of SCI, improve functional recovery, and reduce neuronal apoptosis, microglia activation, and neuroinflammation in rats. Furthermore, our study suggests that NSC-sEVs can regulate apoptosis and inflammatory processes by inducing autophagy. In brief, NSC-sEVs increased the expression of the autophagy marker proteins LC3B and beclin-1, and promoted autophagosome formation. Following NSC-sEV infusion, the SCI area was significantly reduced, and the expression levels of the proapoptotic protein Bax, the apoptosis effector cleaved caspase-3, and the pro-inflammatory cytokines TNF-α, IL-1β, and IL-6 were significantly reduced, whereas the expression level of the anti-apoptotic protein Bcl-2 was upregulated. In the presence of the autophagy inhibitor 3MA, however, these inhibitory effects of NSC-sEVs on apoptosis and neuroinflammation were significantly reversed. Our results show for the first time that NSC-sEV treatment has the potential to reduce neuronal apoptosis, inhibit neuroinflammation, and promote functional recovery in SCI model rats at an early stage by promoting autophagy.