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MiR-125a-5p in MSC-derived small extracellular vesicles alleviates Müller cells injury in diabetic retinopathy by
Cong Liu1, Jinjin Xiang2,3, Yueqin Chen1
1Department of Ophthalmology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, 210008, China.
Abstract:
Diabetic retinopathy (DR) ranks among the primary causes of adult blindness globally. Oxidative stress and mitochondrial dysfunction play a critical role in the progression of DR. Mounting data indicated that small extracellular vesicles (sEVs) of mesenchymal stem cell (MSC) have the ability to transport bioactive chemicals to target cells, leading to changes in their phenotype. Nevertheless, it remains elusive how MSC-derived sEVs regulate oxidative stress and mitochondrial function in DR. MSC-sEVs was intravitreally injected to streptozotocin (STZ)-treated Sprague-Dawley rats to assess the therapeutic effects on DR. The underlying regulatory mechanism was investigated by coculturing advanced glycation end-products (AGEs)-induced rat Müller cells with/without PTP1B overexpression with MSC-sEVs in vitro, with or without miR-125a-5p suppression. Intravitreal injection of MSC-sEVs improved histological morphology and blood-retinal barrier function, alleviated Müller gliosis, decreased PTP1B expression, redox stress and apoptosis in retina of diabetic rat. MSC-sEVs decreased the accumulation of ROS and improved the structure and function of mitochondria of Müller cells with AGEs treatment. Mechanically, MSC-sEVs activated the mitophagy of AGEs-treated Müller cells, represented by an increased expression of the LC3II/LC3I ratio, TOM20, PINK1 and Parkin along with a decreased expression of P62. Importantly, miR-125a-5p inhibitor abolished the protective effects of MSC-sEVs. Furthermore, the overexpression of PTP1B in Müller cells reduced the effects of MSC-sEVs. These findings suggested that miR-125a-5p of MSC-sEVs alleviates Müller cells injury in DR by modulating PINK1/Parkin-mediated mitophagy via PTP1B pathway.
Insights
Mesenchymal stem cell-derived small extracellular vesicles (MSC-sEVs) protect against diabetic retinopathy (DR) by reducing oxidative stress and improving mitochondrial function in Müller cells. This therapy involves miR-125a-5p modulating mitophagy via the PTP1B pathway.
Area of Science:
- Ophthalmology
- Regenerative Medicine
- Cell Biology
Background:
- Diabetic retinopathy (DR) is a leading cause of blindness globally, driven by oxidative stress and mitochondrial dysfunction.
- Mesenchymal stem cell-derived small extracellular vesicles (MSC-sEVs) show therapeutic potential by delivering bioactive cargo.
- The precise mechanisms by which MSC-sEVs mitigate DR-associated cellular damage remain under investigation.
Purpose of the Study:
- To investigate the therapeutic effects of MSC-sEVs on diabetic retinopathy (DR) in a rat model.
- To elucidate the underlying molecular mechanisms involving oxidative stress, mitochondrial function, and mitophagy in Müller cells.
Main Methods:
- MSC-sEVs were intravitreally injected into streptozotocin-induced diabetic rats.
- In vitro studies involved co-culturing advanced glycation end-product (AGEs)-induced rat Müller cells with MSC-sEVs, with manipulations of PTP1B and miR-125a-5p.
- Histological analysis, blood-retinal barrier assessment, oxidative stress markers, mitochondrial function assays, and mitophagy-related protein expression were evaluated.
Main Results:
- MSC-sEVs treatment improved retinal morphology, blood-retinal barrier integrity, and reduced Müller cell gliosis, PTP1B expression, oxidative stress, and apoptosis in diabetic rats.
- MSC-sEVs decreased reactive oxygen species (ROS) accumulation and enhanced mitochondrial structure and function in AGEs-treated Müller cells.
- MSC-sEVs promoted mitophagy in Müller cells, evidenced by altered expression of mitophagy markers (LC3II/LC3I, TOM20, PINK1, Parkin, P62).
Conclusions:
- MSC-sEVs demonstrate significant therapeutic potential for diabetic retinopathy (DR).
- The protective effects are mediated by miR-125a-5p within MSC-sEVs, which activate PINK1/Parkin-dependent mitophagy and downregulate PTP1B in Müller cells.
- This study reveals a novel mechanism for MSC-sEVs in combating DR-induced cellular damage.
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