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 dise...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-γcoactivator-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-1αpathway.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.展开更多
基金supported by the National Natural Science Foundation of China(81971757,82272179)the Advanced Science and Technology Foundation of the Jiangsu Province(BE2021689)+1 种基金Zhenjiang Key Laboratory of High Technology Research on Exosomes Foundation and Transformation Application(ss2018003)Priority Academic Program Development of Jiangsu Higher Education Institutions Project(Phase III).
文摘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-γcoactivator-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-1αpathway.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.
