Engineered mesenchymal stem cell-derived small extracellular vesicles for diabetic retinopathy therapy through HIF-1α/EZH2/PGC-1α pathway.
Engineered mesenchymal stem cell-derived small extracellular vesicles for diabetic retinopathy therapy through HIF-1α/EZH2/PGC-1α pathway.
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DOI：
10.1016/j.bioactmat.2023.11.008
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发表时间：
2024-03
影响因子：
18.9
通讯作者：
中科院分区：
文献类型：
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作者：
糖尿病视网膜病变（DR）是全球范围内致盲的主要原因，治疗选择有限。间充质干细胞衍生的小细胞外囊泡（MSC-sEVs）有望成为视网膜疾病的无细胞疗法。在这项研究中，我们提出的证据表明，玻璃体内注射MSC-sEV改善视网膜功能，减轻视网膜细胞凋亡，炎症和血管生成在db/db小鼠和链脲佐菌素诱导的糖尿病大鼠。机制上，高血糖诱导的缺氧诱导因子-1 α（HIF-1α）激活抑制了三联体基序21（TRIM 21）介导的泛素化和zeste增强子同源物2（EZH 2）的降解，最终通过EZH 2诱导的甲基化修饰导致过氧化物酶体增殖物激活受体-γ共激活因子-1 α（PGC-1α）下调。MSC-sEV中miR-5068和miR-10228的存在靶向HIF-1α/EZH 2/PGC-1α通路。miR-5068和miR-10228的阻断消除了MSC-sEV的视网膜治疗作用。此外，我们设计了具有升高水平的miR-5068和miR-10228的MSC-sEV以增强视网膜修复效率。总之，我们的研究结果为DR进展的机制提供了新的见解，并强调了MSC-sEV，特别是工程MSC-sEV作为DR治疗选择的潜力。MSC-sEV在db/db小鼠和STZ诱导的糖尿病大鼠中发挥视网膜治疗作用。HIF-1α通过EZH 2诱导的甲基化修饰抑制PGC-1α表达HIF-1α阻止TRIM 21介导的EZH 2泛素化和降解。miR-5068和miR-10228通过调节HIF-1α/EZH 2/PGC-1α通路共同介导MSC-sEVs对DR的治疗作用。具有增加水平的miR-5068和miR-10228的工程化MSC-sEV表现出增强的视网膜治疗效率。
Diabetic retinopathy (DR) is a leading cause of blindness worldwide with limited treatment options. Mesenchymal stem cell-derived small extracellular vesicles (MSC-sEVs) hold promise as a cell-free therapy for retinal diseases. In this study, we present evidence that the intravitreal injection of MSC-sEVs improved retinal function and alleviated retinal apoptosis, inflammation, and angiogenesis in both db/db mice and streptozotocin-induced diabetic rats. Mechanistically, hyperglycemia-induced activation of hypoxia-inducible factor-1α (HIF-1α) inhibited the tripartite motif 21 (TRIM21)-mediated ubiquitination and degradation of enhancer of zeste homologue 2 (EZH2), ultimately resulting in the downregulation of peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) through EZH2-induced methylation modification. The presence of miR-5068 and miR-10228 in MSC-sEVs targeted the HIF-1α/EZH2/PGC-1α pathway. The blockade of miR-5068 and miR-10228 abolished the retinal therapeutic effects of MSC-sEVs. Additionally, we engineered MSC-sEVs with elevated levels of miR-5068 and miR-10228 to enhance retinal repair efficiency. Together, our findings provide novel insights into the mechanism underlying DR progress and highlight the potential of MSC-sEVs, especially engineered MSC-sEVs, as a therapeutic option for DR. MSC-sEVs exert retinal therapeutic roles in db/db mice and STZ-induced diabetic rats. HIF-1α inhibits PGC-1α expression through EZH2-induced methylation modification. HIF-1α prevents TRIM21-mediated EZH2 ubiquitination and degradation. MiR-5068 and miR-10228 co-mediate the therapeutic effects of MSC-sEVs on DR by regulating HIF-1α/EZH2/PGC-1α pathway. Engineered MSC-sEVs with increased levels of miR-5068 and miR-10228 exhibit enhanced retinal therapeutic efficiency.
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