Extracellular vesicles released by human retinal pigment epithelium mediate increased polarised secretion of drusen proteins in response to AMD stressors.
Extracellular vesicles released by human retinal pigment epithelium mediate increased polarised secretion of drusen proteins in response to AMD stressors.
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DOI：
10.1002/jev2.12165
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发表时间：
2021-11
影响因子：
16
通讯作者：
Canto-Soler MV
中科院分区：
文献类型：
--
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
年龄相关性黄斑变性（AMD）是全球失明的主要原因。Drusen是AMD病因学的关键因素，调节Drusen生物发生的能力可能导致减缓或停止AMD进展的治疗策略。然而，其潜在的生物发生机制仍然是未知的。在稳态条件下，视网膜色素上皮（RPE）细胞分泌的细胞外囊泡（EVs）富含与AMD病理生理机制相关的蛋白质，包括氧化应激、免疫反应、炎症、补体系统和蛋白组成。此外，我们提供的第一个证据表明，drusen相关蛋白作为RPE细胞分泌的细胞外囊泡的货物，以极化的顶基模式释放。值得注意的是，drusen相关蛋白在稳态条件下表现出独特的定向分泌模式，并且在AMD应激源下这种定向分泌的差异调节。这些观察结果支持了一种精细调节机制的存在，该机制通过EVs调节drusen相关蛋白的定向顶基底分选和分泌，以及其在AMD病理生理机制中的调节。总的来说，我们的研究结果有力地支持了RPE衍生的ev作为drusen蛋白的关键来源和drusen发育和生长的重要贡献者的积极作用。
Age‐related macular degeneration (AMD) is a leading cause of blindness worldwide. Drusen are key contributors to the etiology of AMD and the ability to modulate drusen biogenesis could lead to therapeutic strategies to slow or halt AMD progression. The mechanisms underlying drusen biogenesis, however, remain mostly unknown. Here we demonstrate that under homeostatic conditions extracellular vesicles (EVs) secreted by retinal pigment epithelium (RPE) cells are enriched in proteins associated with mechanisms involved in AMD pathophysiology, including oxidative stress, immune response, inflammation, complement system and drusen composition. Furthermore, we provide first evidence that drusen‐associated proteins are released as cargo of extracellular vesicles secreted by RPE cells in a polarised apical:basal mode. Notably, drusen‐associated proteins exhibited distinctive directional secretion modes in homeostatic conditions and, differential modulation of this directional secretion in response to AMD stressors. These observations underpin the existence of a finely‐tuned mechanism regulating directional apical:basal sorting and secretion of drusen‐associated proteins via EVs, and its modulation in response to mechanisms involved in AMD pathophysiology. Collectively, our results strongly support an active role of RPE‐derived EVs as a key source of drusen proteins and important contributors to drusen development and growth.
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影响因子：
7.3
作者：
Andreu Z;Yáñez-Mó M
通讯作者：
Yáñez-Mó M
影响因子：
3.4
作者：
Becerra, SP;Fariss, RN;Pfeffer, BA
通讯作者：
Pfeffer, BA
影响因子：
4.4
作者：
Blenkinsop, Timothy A.;Saini, Janmeet S.;Stern, Jeffrey H.
通讯作者：
Stern, Jeffrey H.
影响因子：
5.3
作者：
Atienzar-Aroca S;Flores-Bellver M;Serrano-Heras G;Martinez-Gil N;Barcia JM;Aparicio S;Perez-Cremades D;Garcia-Verdugo JM;Diaz-Llopis M;Romero FJ;Sancho-Pelluz J
通讯作者：
Sancho-Pelluz J
影响因子：
3.4
作者：
Anderson, DH;Talaga, KC;Johnson, LV
通讯作者：
Johnson, LV