In the central nervous system (CNS), including in the retina, neuronal-to-glial communication is critical for maintaining tissue homeostasis including signal transmission, transfer of trophic factors, and in the modulation of inflammation. Extracellular vesicle (EV)-mediated transport of molecular messages to regulate these processes has been suggested as a mechanism by which bidirectional communication between neuronal and glial cells can occur. In this work we employed multiomics integration to investigate the role of EV communication pathways from neurons to glial cells within the CNS, using the mouse retina as a readily accessible representative CNS tissue. Further, using a well-established model of degeneration, we aimed to uncover how dysregulation of homeostatic messaging between neurons and glia via EV can result in retinal and neurodegenerative diseases. EV proteomics, glia microRNA (miRNA) Open Array and small RNA sequencing, and retinal single cell sequencing were performed, with datasets integrated and analysed computationally. Results demonstrated that exogenous transfer of neuronal miRNA to glial cells was mediated by EV and occurred as a targeted response during degeneration to modulate gliotic inflammation. Taken together, our results support a model of neuronal-to-glial communication via EV, which could be harnessed for therapeutic targeting to slow the progression of retinal-, and neuro-degenerations of the CNS.

中文翻译：

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多组学整合揭示了退化过程中神经元-细胞外囊泡神经胶质细胞反应的协调

在中枢神经系统 (CNS)（包括视网膜）中，神经元与神经胶质的通讯对于维持组织稳态（包括信号传输、营养因子的转移和炎症调节）至关重要。细胞外囊泡（EV）介导的分子信息传输来调节这些过程已被认为是神经元和神经胶质细胞之间可以发生双向通信的机制。在这项工作中，我们采用多组学整合来研究中枢神经系统内从神经元到神经胶质细胞的 EV 通信途径的作用，使用小鼠视网膜作为易于接近的代表性中枢神经系统组织。此外，利用成熟的变性模型，我们旨在揭示神经元和神经胶质细胞之间通过 EV 进行的稳态消息传递失调如何导致视网膜和神经退行性疾病。进行了 EV 蛋白质组学、神经胶质细胞 microRNA (miRNA) 开放阵列和小 RNA 测序以及视网膜单细胞测序，并通过计算整合和分析了数据集。结果表明，神经元 miRNA 向神经胶质细胞的外源转移是由 EV 介导的，并且作为变性过程中的靶向反应而发生，以调节神经胶质炎症。总而言之，我们的结果支持通过 EV 进行神经元与神经胶质细胞通讯的模型，该模型可用于靶向治疗，以减缓中枢神经系统视网膜和神经变性的进展。