MSC-derived small extracellular vesicles attenuate diabetic retinopathy through miR-29a-3p regulated microglia
Jun Tong1, Yueqin Chen2, Ye Zhang2
1Department of Ophthalmology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China; Department of Ophthalmology, Northern Jiangsu People's Hospital, Yangzhou University, Yangzhou, China.
Abstract:
Diabetic retinopathy (DR), considered as a neurovascular disorder, significantly causes permanent vision loss and blindness worldwide among working-age adults. The inflammation caused by M1-like microglia is involved in DR. Mesenchymal stem cell (MSC)-derived small extracellular vesicles (sEVs) is an attractive candidate for inflammation modulation. However, the regulatory effect of sEVs secreted by MSCs on M1 differentiation of microglia in diabetic retinopathy has not been thoroughly investigated. In this study, intravitreal injection of sEVs reduced retinal inflammation, mitigated vascular leakage, and suppressed M1-like microglia via the HMGB1/TLR4 signaling pathway. Based on MSC-sEVs miRNA sequencing, bioinformatics prediction, and dual-luciferase reporter assay, miR-29a-3p was identified as a key effector in the modulation of M1-like microglia through the down-regulation of HMGB1. The silencing of miR-29a-3p in MSC-sEVs negated their therapeutic efficacy in STZ-induced diabetic rats and human microglial cells (HMC3) treated with advanced glycation end products (AGEs). Silencing miR-29a-3p in MSC-sEVs reversed the therapeutic effects of MSC-sEVs on STZ-induced rats and advanced glycation end products (AGEs)-treated HMC3. Additionally, overexpression of miR-29a-3p could suppress M1-like microglia, which could be effectively reversed by overexpressing HMGB1. Overall, this study demonstrated that MSC-sEVs carrying miR-29a-3p attenuate retinal injury in diabetic rats by reducing M1 microglia polarization through the targeting of HMGB1, thereby reducing inflammation and protecting the blood-retinal barrier (BRB). MSC-sEVs and miRNAs may be explored as promising therapeutic targets for DR.
Insights
Mesenchymal stem cell-derived small extracellular vesicles (sEVs) carrying miR-29a-3p reduce diabetic retinopathy (DR) by suppressing M1 microglia inflammation via the HMGB1 pathway. This finding offers new therapeutic targets for vision loss in DR patients.
Area of Science:
- Ophthalmology
- Neuroscience
- Stem Cell Biology
Background:
- Diabetic retinopathy (DR) is a leading cause of vision loss, driven by neuroinflammation involving M1-like microglia.
- Mesenchymal stem cell-derived small extracellular vesicles (sEVs) show potential for modulating inflammation, but their specific role in DR requires investigation.
Purpose of the Study:
- To investigate the therapeutic effect of MSC-sEVs on M1 microglia polarization in diabetic retinopathy.
- To identify the specific miRNA within MSC-sEVs responsible for regulating M1 microglia differentiation and its mechanism of action.
Main Methods:
- Intravitreal injection of sEVs in STZ-induced diabetic rats and advanced glycation end product (AGE)-treated human microglial cells (HMC3).
- miRNA sequencing of MSC-sEVs, bioinformatics prediction, and dual-luciferase reporter assay to identify key miRNAs and their targets.
- Silencing and overexpression of miR-29a-3p and HMGB1 in MSC-sEVs and HMC3 cells.
Main Results:
- MSC-sEVs treatment reduced retinal inflammation, vascular leakage, and M1-like microglia via the HMGB1/TLR4 pathway.
- miR-29a-3p was identified as a key miRNA in MSC-sEVs that down-regulates HMGB1, suppressing M1 microglia polarization.
- Silencing miR-29a-3p abrogated the therapeutic effects of MSC-sEVs, while its overexpression suppressed M1 microglia, an effect reversed by HMGB1 overexpression.
Conclusions:
- MSC-sEVs carrying miR-29a-3p attenuate DR by inhibiting M1 microglia polarization through targeting HMGB1.
- This mechanism reduces retinal inflammation and protects the blood-retinal barrier (BRB), highlighting MSC-sEVs and miRNAs as potential therapeutic strategies for DR.
