Hypoxic preconditioned MSCs-derived small extracellular vesicles for photoreceptor protection in retinal degeneration
Abstract Photoreceptor apoptosis is an important pathogenesis of retinal degeneration and a primary cause of vision loss with limited treatment methods. Mesenchymal stem/stromal cells-derived small extracellular vesicles (MSC-sEVs) have shown therapeutic value in various ocular disorders. Recent stu...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2023-11-01
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| Series: | Journal of Nanobiotechnology |
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| Online Access: | https://doi.org/10.1186/s12951-023-02225-2 |
| _version_ | 1797451656585019392 |
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| author | Yuntong Sun Yuntao Sun Shenyuan Chen Yifan Yu Yongjun Ma Fengtian Sun |
| author_facet | Yuntong Sun Yuntao Sun Shenyuan Chen Yifan Yu Yongjun Ma Fengtian Sun |
| author_sort | Yuntong Sun |
| collection | DOAJ |
| description | Abstract Photoreceptor apoptosis is an important pathogenesis of retinal degeneration and a primary cause of vision loss with limited treatment methods. Mesenchymal stem/stromal cells-derived small extracellular vesicles (MSC-sEVs) have shown therapeutic value in various ocular disorders. Recent studies have revealed that hypoxic preconditioning can improve the effectiveness of MSC-sEVs in tissue regeneration. However, whether hypoxic preconditioned MSC-sEVs (Hyp-sEVs) exert superior effects on photoreceptor protection relative to normoxic conditioned MSC-sEVs (Nor-sEVs) remains unclear. Here, we reported that Hyp-sEVs further improved retinal structure, recovered retinal function, and suppressed photoreceptor apoptosis in N-methyl-N-nitrosourea (MNU)-induced mouse model compared with Nor-sEVs. Hyp-sEVs also exhibited enhanced anti-apoptotic roles in MNU-provoked 661 W cell injury in vitro. We then analyzed the protein profiles of Nor-sEVs and Hyp-sEVs by LC-MS/MS and found that growth-associated protein 43 (GAP43) was enriched in Hyp-sEVs. The knockdown of GAP43 abolished the retinal therapeutic effects of Hyp-sEVs. Mechanistically, hypoxic stimulation-induced hypoxia-inducible factor-1α (HIF-1α) activation was responsible for preventing tripartite motif-containing protein 25 (TRIM25)-mediated GAP43 ubiquitination and degradation, leading to the upregulation of GAP43 in Hyp-sEVs. Together, our findings uncover the efficacy and mechanism of Hyp-sEVs-based photoreceptor protection and highlight the potential of Hyp-sEVs as optimized therapeutics for retinal degeneration. Graphical abstract |
| first_indexed | 2024-03-09T14:57:38Z |
| format | Article |
| id | doaj.art-f604d3f8bb58473ab3164da635f99362 |
| institution | Directory Open Access Journal |
| issn | 1477-3155 |
| language | English |
| last_indexed | 2024-03-09T14:57:38Z |
| publishDate | 2023-11-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Nanobiotechnology |
| spelling | doaj.art-f604d3f8bb58473ab3164da635f993622023-11-26T14:08:40ZengBMCJournal of Nanobiotechnology1477-31552023-11-0121111710.1186/s12951-023-02225-2Hypoxic preconditioned MSCs-derived small extracellular vesicles for photoreceptor protection in retinal degenerationYuntong Sun0Yuntao Sun1Shenyuan Chen2Yifan Yu3Yongjun Ma4Fengtian Sun5Department of Clinical Laboratory, Affiliated Jinhua Hospital, Zhejiang University School of MedicineJiangsu Province Key Laboratory of Medical Science and Laboratory Medicine, Department of Laboratory Medicine, School of Medicine, Jiangsu UniversityJiangsu Province Key Laboratory of Medical Science and Laboratory Medicine, Department of Laboratory Medicine, School of Medicine, Jiangsu UniversityJiangsu Province Key Laboratory of Medical Science and Laboratory Medicine, Department of Laboratory Medicine, School of Medicine, Jiangsu UniversityDepartment of Clinical Laboratory, Affiliated Jinhua Hospital, Zhejiang University School of MedicineDepartment of Clinical Laboratory, Affiliated Jinhua Hospital, Zhejiang University School of MedicineAbstract Photoreceptor apoptosis is an important pathogenesis of retinal degeneration and a primary cause of vision loss with limited treatment methods. Mesenchymal stem/stromal cells-derived small extracellular vesicles (MSC-sEVs) have shown therapeutic value in various ocular disorders. Recent studies have revealed that hypoxic preconditioning can improve the effectiveness of MSC-sEVs in tissue regeneration. However, whether hypoxic preconditioned MSC-sEVs (Hyp-sEVs) exert superior effects on photoreceptor protection relative to normoxic conditioned MSC-sEVs (Nor-sEVs) remains unclear. Here, we reported that Hyp-sEVs further improved retinal structure, recovered retinal function, and suppressed photoreceptor apoptosis in N-methyl-N-nitrosourea (MNU)-induced mouse model compared with Nor-sEVs. Hyp-sEVs also exhibited enhanced anti-apoptotic roles in MNU-provoked 661 W cell injury in vitro. We then analyzed the protein profiles of Nor-sEVs and Hyp-sEVs by LC-MS/MS and found that growth-associated protein 43 (GAP43) was enriched in Hyp-sEVs. The knockdown of GAP43 abolished the retinal therapeutic effects of Hyp-sEVs. Mechanistically, hypoxic stimulation-induced hypoxia-inducible factor-1α (HIF-1α) activation was responsible for preventing tripartite motif-containing protein 25 (TRIM25)-mediated GAP43 ubiquitination and degradation, leading to the upregulation of GAP43 in Hyp-sEVs. Together, our findings uncover the efficacy and mechanism of Hyp-sEVs-based photoreceptor protection and highlight the potential of Hyp-sEVs as optimized therapeutics for retinal degeneration. Graphical abstracthttps://doi.org/10.1186/s12951-023-02225-2Photoreceptor apoptosisRetinal degenerationSmall extracellular vesiclesMesenchymal stem/stromal cellsHypoxiaGAP43 |
| spellingShingle | Yuntong Sun Yuntao Sun Shenyuan Chen Yifan Yu Yongjun Ma Fengtian Sun Hypoxic preconditioned MSCs-derived small extracellular vesicles for photoreceptor protection in retinal degeneration Journal of Nanobiotechnology Photoreceptor apoptosis Retinal degeneration Small extracellular vesicles Mesenchymal stem/stromal cells Hypoxia GAP43 |
| title | Hypoxic preconditioned MSCs-derived small extracellular vesicles for photoreceptor protection in retinal degeneration |
| title_full | Hypoxic preconditioned MSCs-derived small extracellular vesicles for photoreceptor protection in retinal degeneration |
| title_fullStr | Hypoxic preconditioned MSCs-derived small extracellular vesicles for photoreceptor protection in retinal degeneration |
| title_full_unstemmed | Hypoxic preconditioned MSCs-derived small extracellular vesicles for photoreceptor protection in retinal degeneration |
| title_short | Hypoxic preconditioned MSCs-derived small extracellular vesicles for photoreceptor protection in retinal degeneration |
| title_sort | hypoxic preconditioned mscs derived small extracellular vesicles for photoreceptor protection in retinal degeneration |
| topic | Photoreceptor apoptosis Retinal degeneration Small extracellular vesicles Mesenchymal stem/stromal cells Hypoxia GAP43 |
| url | https://doi.org/10.1186/s12951-023-02225-2 |
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