Engineered mesenchymal stem cell-derived small extracellular vesicles for diabetic retinopathy therapy through HIF-1α/EZH2/PGC-1α pathway

Fengtian Sun; Yuntong Sun; Xiaoling Wang; Junyan Zhu; Shenyuan Chen; Yifan Yu; Mengyao Zhu; Wenrong Xu; Hui Qian

doi:10.1016/j.bioactmat.2023.11.008

Engineered mesenchymal stem cell-derived small extracellular vesicles for diabetic retinopathy therapy through HIF-1α/EZH2/PGC-1α pathway

Bioact Mater. 2023 Nov 28:33:444-459. doi: 10.1016/j.bioactmat.2023.11.008. eCollection 2024 Mar.

Authors

Fengtian Sun^{1

2}, Yuntong Sun^{1

2}, Xiaoling Wang^{1

3}, Junyan Zhu¹, Shenyuan Chen¹, Yifan Yu¹, Mengyao Zhu¹, Wenrong Xu¹, Hui Qian^{1

4}

Affiliations

¹ Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, Department of Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, 212013, Jiangsu, China.
² Department of Clinical Laboratory, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, 321000, Zhejiang, China.
³ Department of Laboratory Medicine, Zhongshan Hospital (Xiamen), Fudan University, Xiamen, 361006, Fujian, China.
⁴ NHC Key Laboratory of Medical Embryogenesis and Developmental Molecular Biology & Shanghai Key Laboratory of Embryo and Reproduction Engineering, Shanghai, 200040, China.

Abstract

Diabetic retinopathy (DR) is a leading cause of blindness worldwide with limited treatment options. Mesenchymal stem cell-derived small extracellular vesicles (MSC-sEVs) hold promise as a cell-free therapy for retinal diseases. In this study, we present evidence that the intravitreal injection of MSC-sEVs improved retinal function and alleviated retinal apoptosis, inflammation, and angiogenesis in both db/db mice and streptozotocin-induced diabetic rats. Mechanistically, hyperglycemia-induced activation of hypoxia-inducible factor-1α (HIF-1α) inhibited the tripartite motif 21 (TRIM21)-mediated ubiquitination and degradation of enhancer of zeste homologue 2 (EZH2), ultimately resulting in the downregulation of peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) through EZH2-induced methylation modification. The presence of miR-5068 and miR-10228 in MSC-sEVs targeted the HIF-1α/EZH2/PGC-1α pathway. The blockade of miR-5068 and miR-10228 abolished the retinal therapeutic effects of MSC-sEVs. Additionally, we engineered MSC-sEVs with elevated levels of miR-5068 and miR-10228 to enhance retinal repair efficiency. Together, our findings provide novel insights into the mechanism underlying DR progress and highlight the potential of MSC-sEVs, especially engineered MSC-sEVs, as a therapeutic option for DR.

Keywords: Diabetic retinopathy; Engineering; Mesenchymal stem cell; MiRNA; Small extracellular vesicles.