Retinal pigment epithelium extracellular vesicles are potent inducers of age-related macular degeneration disease phenotype in the outer retina.
Retinal pigment epithelium extracellular vesicles are potent inducers of age-related macular degeneration disease phenotype in the outer retina.
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视网膜色素上皮细胞外囊泡是外视网膜中与年龄相关的黄斑变性疾病表型的有效诱导剂。
DOI：
10.1002/jev2.12295
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发表时间：
2022-12
影响因子：
16
通讯作者：
中科院分区：
文献类型：
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作者：
年龄相关性黄斑变性（AMD）是导致失明的主要原因。视力丧失由视网膜色素上皮（RPE）和光感受器萎缩和/或视网膜和脉络膜血管生成引起。在这里，我们使用具有补体因子H Y 402 H高风险多态性的AMD患者特异性RPE细胞来对细胞外囊泡（EV）、其货物和在疾病病理学中的作用进行全面分析。我们发现AMD RPE的特征在于增强的极化EV分泌。多组学分析表明，AMD RPE EV携带RNA、蛋白质和脂质，其介导关键的AMD特征，包括氧化应激、细胞骨架功能障碍、血管生成和玻璃疣积累。此外，AMD RPE EV诱导淀粉样蛋白原纤维形成，揭示了它们在玻璃疣形成中的作用。我们证明，对照RPE暴露于AMD RPE顶端EV导致AMD特征的获得，例如应激空泡、细胞骨架不稳定和细胞核形态异常。用顶端AMD RPE EV治疗视网膜类器官导致神经上皮破坏和细胞保护性α B晶状体蛋白免疫阳性细胞的出现，其中一些共表达视网膜祖细胞标志物Pax 6/Vsx 2，表明损伤诱导的再生途径激活。这些发现表明AMD RPE EV是邻近RPE和视网膜细胞中AMD表型的有效诱导剂。
Age‐related macular degeneration (AMD) is a leading cause of blindness. Vision loss is caused by the retinal pigment epithelium (RPE) and photoreceptors atrophy and/or retinal and choroidal angiogenesis. Here we use AMD patient‐specific RPE cells with the Complement Factor H Y402H high‐risk polymorphism to perform a comprehensive analysis of extracellular vesicles (EVs), their cargo and role in disease pathology. We show that AMD RPE is characterised by enhanced polarised EV secretion. Multi‐omics analyses demonstrate that AMD RPE EVs carry RNA, proteins and lipids, which mediate key AMD features including oxidative stress, cytoskeletal dysfunction, angiogenesis and drusen accumulation. Moreover, AMD RPE EVs induce amyloid fibril formation, revealing their role in drusen formation. We demonstrate that exposure of control RPE to AMD RPE apical EVs leads to the acquisition of AMD features such as stress vacuoles, cytoskeletal destabilization and abnormalities in the morphology of the nucleus. Retinal organoid treatment with apical AMD RPE EVs leads to disrupted neuroepithelium and the appearance of cytoprotective alpha B crystallin immunopositive cells, with some co‐expressing retinal progenitor cell markers Pax6/Vsx2, suggesting injury‐induced regenerative pathways activation. These findings indicate that AMD RPE EVs are potent inducers of AMD phenotype in the neighbouring RPE and retinal cells.
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影响因子：
16
作者：
Flores-Bellver M;Mighty J;Aparicio-Domingo S;Li KV;Shi C;Zhou J;Cobb H;McGrath P;Michelis G;Lenhart P;Bilousova G;Heissel S;Rudy MJ;Coughlan C;Goodspeed AE;Becerra SP;Redenti S;Canto-Soler MV
通讯作者：
Canto-Soler MV
影响因子：
14
作者：
Dorgau, Birthe;Felemban, Majed;Lako, Majlinda
通讯作者：
Lako, Majlinda
DOI：
10.1016/j.bbapap.2018.07.004
发表时间：
2018-10-01
影响因子：
3.2
作者：
Gaspar, Ricardo;Pallbo, Jon;Sparr, Emma
通讯作者：
Sparr, Emma
影响因子：
3.4
作者：
Gouras, Peter;Brown, Kristy;Neuringer, Martha
通讯作者：
Neuringer, Martha
DOI：
10.1073/pnas.222551899
发表时间：
2002-11-12
影响因子：
11.1
作者：
Crabb, JW;Miyagi, M;Hollyfield, JG
通讯作者：
Hollyfield, JG