PMID- 35841055 OWN - NLM STAT- MEDLINE DCOM- 20220719 LR - 20220729 IS - 1757-6512 (Electronic) IS - 1757-6512 (Linking) VI - 13 IP - 1 DP - 2022 Jul 15 TI - Mesenchymal stem cells-derived small extracellular vesicles alleviate diabetic retinopathy by delivering NEDD4. PG - 293 LID - 10.1186/s13287-022-02983-0 [doi] LID - 293 AB - BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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. CI - (c) 2022. The Author(s). FAU - Sun, Fengtian AU - Sun F AD - Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, 212013, Jiangsu, China. FAU - Sun, Yuntong AU - Sun Y AD - Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, 212013, Jiangsu, China. FAU - Zhu, Junyan AU - Zhu J AD - Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, 212013, Jiangsu, China. FAU - Wang, Xiaoling AU - Wang X AD - Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, 212013, Jiangsu, China. FAU - Ji, Cheng AU - Ji C AD - Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, 212013, Jiangsu, China. FAU - Zhang, Jiahui AU - Zhang J AD - Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, 212013, Jiangsu, China. FAU - Chen, Shenyuan AU - Chen S AD - Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, 212013, Jiangsu, China. FAU - Yu, Yifan AU - Yu Y AD - Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, 212013, Jiangsu, China. FAU - Xu, Wenrong AU - Xu W AD - Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, 212013, Jiangsu, China. icls@ujs.edu.cn. FAU - Qian, Hui AU - Qian H AUID- ORCID: 0000-0002-0098-3196 AD - Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, 212013, Jiangsu, China. lstmmmlst@163.com. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20220715 PL - England TA - Stem Cell Res Ther JT - Stem cell research & therapy JID - 101527581 RN - 0 (NF-E2-Related Factor 2) RN - EC 2.3.2.26 (Nedd4 Ubiquitin Protein Ligases) RN - EC 2.3.2.26 (Nedd4 protein, rat) RN - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt) SB - IM MH - Animals MH - *Diabetes Mellitus, Experimental/pathology/therapy MH - *Diabetic Retinopathy/therapy MH - *Extracellular Vesicles/metabolism MH - *Mesenchymal Stem Cells/metabolism MH - NF-E2-Related Factor 2/genetics/metabolism MH - *Nedd4 Ubiquitin Protein Ligases/administration & dosage MH - Proto-Oncogene Proteins c-akt/metabolism MH - Rats PMC - PMC9284871 OTO - NOTNLM OT - AKT OT - DR OT - MSC-sEV OT - NEDD4 OT - NRF2 OT - PTEN OT - RPE COIS- The authors declare that they have no competing interests. EDAT- 2022/07/16 06:00 MHDA- 2022/07/20 06:00 PMCR- 2022/07/15 CRDT- 2022/07/15 23:47 PHST- 2021/12/24 00:00 [received] PHST- 2022/05/29 00:00 [accepted] PHST- 2022/07/15 23:47 [entrez] PHST- 2022/07/16 06:00 [pubmed] PHST- 2022/07/20 06:00 [medline] PHST- 2022/07/15 00:00 [pmc-release] AID - 10.1186/s13287-022-02983-0 [pii] AID - 2983 [pii] AID - 10.1186/s13287-022-02983-0 [doi] PST - epublish SO - Stem Cell Res Ther. 2022 Jul 15;13(1):293. doi: 10.1186/s13287-022-02983-0.