Macrophages play major roles in the pathophysiology of various neurological disorders, being involved in seemingly opposing processes such as lesion progression and resolution. Yet, the molecular mechanisms that drive their harmful and benign effector functions remain poorly understood. Here, we demonstrate that extracellular vesicles (EVs) secreted by repair-associated macrophages (RAMs) enhance remyelination ex vivo and in vivo by promoting the differentiation of oligodendrocyte precursor cells (OPCs). Guided by lipidomic analysis and applying cholesterol depletion and enrichment strategies, we find that EVs released by RAMs show markedly elevated cholesterol levels and that cholesterol abundance controls their reparative impact on OPC maturation and remyelination. Mechanistically, EV-associated cholesterol was found to promote OPC differentiation predominantly through direct membrane fusion. Collectively, our findings highlight that EVs are essential for cholesterol trafficking in the brain and that changes in cholesterol abundance support the reparative impact of EVs released by macrophages in the brain, potentially having broad implications for therapeutic strategies aimed at promoting repair in neurodegenerative disorders.

中文翻译：

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细胞外囊泡相关胆固醇支持大脑巨噬细胞的再生功能

巨噬细胞在各种神经系统疾病的病理生理学中发挥着重要作用，参与看似相反的过程，例如病变进展和消退。然而，驱动其有害和良性效应功能的分子机制仍然知之甚少。在这里，我们证明修复相关巨噬细胞（RAM）分泌的细胞外囊泡（EV）通过促进少突胶质细胞前体细胞（OPC）的分化来增强离体和体内髓鞘再生。在脂质组学分析和应用胆固醇消耗和富集策略的指导下，我们发现 RAM 释放的 EV 显示出明显升高的胆固醇水平，并且胆固醇丰度控制着它们对 OPC 成熟和髓鞘再生的修复影响。从机制上讲，EV 相关胆固醇主要通过直接膜融合促进 OPC 分化。总的来说，我们的研究结果强调，EV 对于大脑中的胆固醇运输至关重要，并且胆固醇丰度的变化支持大脑中巨噬细胞释放的 EV 的修复作用，这可能对旨在促进神经退行性疾病修复的治疗策略产生广泛影响。