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Updated: Jul 10, 2025
Author Spotlight: Advancing Vision Restoration - Stem Cell-Based Therapy for Retinal Diseases
Published on: October 6, 2023
Hypoxic preconditioned MSCs-derived small extracellular vesicles for photoreceptor protection in retinal degeneration
Yuntong Sun1, Yuntao Sun2, Shenyuan Chen2
1Department of Clinical Laboratory, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, 321000, Zhejiang, China.
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.
Insights
Hypoxic preconditioned mesenchymal stem/stromal cells-derived small extracellular vesicles (Hyp-sEVs) offer superior photoreceptor protection against retinal degeneration compared to normoxic conditioned MSC-sEVs (Nor-sEVs). This enhancement is mediated by upregulated growth-associated protein 43 (GAP43) in Hyp-sEVs.
Area of Science:
- Ophthalmology
- Regenerative Medicine
- Cell Biology
Background:
- Photoreceptor apoptosis drives retinal degeneration and vision loss, with limited therapeutic options.
- Mesenchymal stem/stromal cells-derived small extracellular vesicles (MSC-sEVs) show promise for ocular disorders.
- Hypoxic preconditioning may enhance MSC-sEV therapeutic efficacy.
Purpose of the Study:
- To investigate if hypoxic preconditioned MSC-sEVs (Hyp-sEVs) provide superior photoreceptor protection compared to normoxic MSC-sEVs (Nor-sEVs).
- To elucidate the underlying molecular mechanisms of Hyp-sEVs' therapeutic effects in retinal degeneration.
Main Methods:
- Comparison of Hyp-sEVs and Nor-sEVs in an N-methyl-N-nitrosourea (MNU)-induced mouse model of retinal degeneration.
- In vitro assessment of anti-apoptotic effects on MNU-provoked 661W cells.
- Proteomic analysis (LC-MS/MS) of sEVs and molecular mechanism investigation involving GAP43, HIF-1α, and TRIM25.
Main Results:
- Hyp-sEVs significantly improved retinal structure, function, and suppressed photoreceptor apoptosis compared to Nor-sEVs.
- Hyp-sEVs demonstrated enhanced anti-apoptotic activity in vitro.
- Growth-associated protein 43 (GAP43) was enriched in Hyp-sEVs, and its knockdown abolished therapeutic effects.
- Hypoxia-inducible factor-1α (HIF-1α) activation prevented TRIM25-mediated GAP43 degradation, leading to GAP43 upregulation in Hyp-sEVs.
Conclusions:
- Hyp-sEVs offer superior therapeutic potential for photoreceptor protection in retinal degeneration compared to Nor-sEVs.
- Upregulation of GAP43, mediated by HIF-1α and TRIM25, is a key mechanism for Hyp-sEVs' enhanced efficacy.
- Hyp-sEVs represent a promising optimized therapeutic strategy for retinal degeneration.
