期刊
STEM CELLS
卷 -, 期 -, 页码 -出版社
OXFORD UNIV PRESS
DOI: 10.1093/stmcls/sxad078
关键词
diabetic retinopathy; mesenchymal stem cells; small extracellular vesicles; microRNA; NLRP3
This study investigated the use of mesenchymal stem cell (MSC)-derived small extracellular vesicles (sEVs) to alleviate diabetic retinopathy (DR) by inhibiting the activation of NLRP3 inflammasome through delivering miR-22-3p. The results showed that MSC-sEVs effectively reduced retinal inflammation and improved histological morphology and blood-retinal barrier function in diabetic rats. These findings suggest that MSC-sEVs may be a potential therapeutic method for DR.
Purpose This study aimed to investigate the effect of mesenchymal stem cell (MSC)-derived small extracellular vesicles (sEVs) on diabetic retinopathy (DR) and its underlying mechanism.Methods In vivo, MSC-sEVs were injected intravitreally into diabetic rats to determine the therapeutic efficacy. In vitro, MSC-sEVs with/without miR-22-3p inhibition were cocultured with advanced glycation end-products (AGEs)-induced microglia with/without NLRP3 overexpression to explore the molecular mechanism.Results In vivo, MSC-sEVs inhibited NLRP3 inflammasome activation, suppressed microglial activation, decreased inflammatory cytokines levels in the retina, and alleviated DR as evidenced by improved histological morphology and blood-retinal barrier function. Based on miRNA sequencing of MSC-sEVs, bioinformatic software, and dual-luciferase reporter assay, miR-22-3p stood out as the critical molecule for the role of MSC-sEVs in regulating NLRP3 inflammasome activation. Diabetic rats had lower level of miR-22-3p in their retina than those of control and sEV-treated rats. Confocal microscopy revealed that sEV could be internalized by microglia both in vivo and in vitro. In vitro, compared with sEV, the anti-inflammation effect of sEVmiR-22-3p(-) on AGEs-induced microglia was compromised, as they gave a lower suppression of NLRP3 inflammasome activation and inflammatory cytokines. In addition, NLRP3 overexpression in microglia damped the anti-inflammatory effect of sEV.Conclusion These results indicated that MSC-sEVs alleviated DR via delivering miR-22-3p to inhibit NLRP3 inflammasome activation. Our findings indicate that MSC-sEVs might be a potential therapeutic method for DR. MSC-sEV-miR-22-3p targets NLRP3, suppresses the activation of NLRP3 inflammasome in microglia, alleviates retinal inflammation, and eventually attenuates BRB breakdown and mitigates DR. Abbreviations: MSC: mesenchymal stem cell; sEV: small extracellular vesicle; BRB: blood-retinal barrier.
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