Mesenchymal stem cells-derived small extracellular vesicles alleviate diabetic retinopathy by delivering NEDD4.
Mesenchymal stem cells-derived small extracellular vesicles alleviate diabetic retinopathy by delivering NEDD4.
复制标题
间充质干细胞衍生的小细胞外囊泡通过递送NEDD4来减轻糖尿病性视网膜病。
DOI：
10.1186/s13287-022-02983-0
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发表时间：
2022-07-15
影响因子：
7.5
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中科院分区：
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糖尿病视网膜病变（diabetic retinopathy，DR）是导致视力下降和严重失明的主要原因之一，其特征是早期视网膜氧化应激加重和细胞凋亡。新兴的研究表明，间充质干细胞衍生的小细胞外囊泡（MSC-sEV）治疗代表了一种有前途的无细胞方法，以减轻眼部疾病。然而，MSC-sEV在DR中的修复作用在很大程度上仍不清楚。本研究旨在探讨MSC-sEV在高糖诱导的视网膜变性中的作用及其机制。体内实验采用链脲佐菌素（STZ）建立糖尿病大鼠模型，玻璃体内注射MSC-sEV，观察其治疗效果。在高糖（HG）培养液中培养视网膜色素上皮（RPE）细胞，观察MSC sEV处理后细胞活力和抗氧化能力的变化。通过检测MSC-sEV处理的RPE细胞中细胞信号通路的反应，探讨MSC-sEV的作用机制。质谱分析显示介导MSC-sEV作用的生物活性蛋白。玻璃体内注射MSC-sEV可引起STZ诱导的DR大鼠模型的抗氧化作用，并对抗视网膜细胞凋亡。MSC-sEV处理还降低了HG条件下体外培养的RPE细胞的氧化水平，增强了细胞的增殖能力。进一步的研究表明，磷酸酶和张力蛋白同源物（PTEN）水平的增加抑制了HG培养基刺激的RPE细胞中AKT磷酸化和核因子红细胞2相关因子2（NRF 2）的表达，这可以被MSC-sEV干预逆转。通过质谱分析，我们说明MSC-sEV递送的神经元前体细胞表达的发育下调的4（NEDD 4）可以引起PTEN泛素化和降解，激活AKT信号传导并上调NRF 2水平以防止DR进展。此外，NEDD 4敲低损害了MSC-sEV介导的视网膜治疗作用。我们的研究结果表明，MSC-sEV通过NEDD 4诱导的对PTEN/AKT/NRF 2信号通路的调节来改善DR，从而揭示了基于MSC-sEV的视网膜保护的效率和机制，并为DR的治疗提供了新的见解。在线版本包含补充材料，可在10.1186/s13287-022-02983-0获得。
As a leading cause of vision decline and severe blindness in adults, diabetic retinopathy (DR) is characterized by the aggravation of retinal oxidative stress and apoptosis in the early stage. Emerging studies reveal that mesenchymal stem cells-derived small extracellular vesicles (MSC-sEV) treatment represents a promising cell-free approach to alleviate ocular disorders. However, the repairing effects of MSC-sEV in DR remain largely unclear. This study aimed at exploring the role and the underlying mechanism of MSC-sEV in hyperglycemia-induced retinal degeneration. In vivo, we used streptozotocin (STZ) to establish diabetic rat model, followed by the intravitreal injection of MSC-sEV to determine the curative effect. The cell viability and antioxidant capacity of retinal pigment epithelium (RPE) cells stimulated with high-glucose (HG) medium after MSC-sEV treatment were analyzed in vitro. By detecting the response of cell signaling pathways in MSC-sEV-treated RPE cells, we explored the functional mechanism of MSC-sEV. Mass spectrometry was performed to reveal the bioactive protein which mediated the role of MSC-sEV. The intravitreal injection of MSC-sEV elicited antioxidant effects and counteracted retinal apoptosis in STZ-induced DR rat model. MSC-sEV treatment also reduced the oxidative level and enhanced the proliferation ability of RPE cells cultured in HG conditions in vitro. Further studies showed that the increased level of phosphatase and tensin homolog (PTEN) inhibited AKT phosphorylation and nuclear factor erythroid 2-related factor 2 (NRF2) expression in RPE cells stimulated with HG medium, which could be reversed by MSC-sEV intervention. Through mass spectrometry, we illustrated that MSC-sEV-delivered neuronal precursor cell-expressed developmentally downregulated 4 (NEDD4) could cause PTEN ubiquitination and degradation, activate AKT signaling and upregulate NRF2 level to prevent DR progress. Moreover, NEDD4 knockdown impaired MSC-sEV-mediated retinal therapeutic effects. Our findings indicated that MSC-sEV ameliorated DR through NEDD4-induced regulation on PTEN/AKT/NRF2 signaling pathway, thus revealing the efficiency and mechanism of MSC-sEV-based retinal protection and providing new insights into the treatment of DR. The online version contains supplementary material available at 10.1186/s13287-022-02983-0.