Mesenchymal Stem Cells-derived Exosomes Alleviate Senescence of Retinal Pigment Epithelial Cells by Activating PI3K/AKT-Nrf2 Signaling Pathway in Early Diabetic Retinopathy

Diabetic retinopathy (DR) is a major cause of vision loss and blindness in adults. Cellular senescence was involved in the pathogenesis of early-stage DR and is positively correlated with progression. Thus, our study aimed at exploring the effect and potential mechanism of Mesenchymal stem cells-derived exosomes (MSCs-EXOs) on Retinal Pigment Epithelial (RPE) cells senescence at an early stage of DR in vivo and in vitro. ARPE-19 cells were incubated in high glucose (HG) medium mixed with MSCs-EXOs to observe the changes in cell viability. Senescence-associated β-galactosidase (SA-β-gal) staining, Western blot and qRT-PCR were used to assess the expression of senescence-related genes and antioxidant mediators. Quantitative Real-Time polymerase chain reaction (qRT-PCR), Optical coherence tomography (OCT) Hematoxylin and eosin (HE) staining and Electroretinogram (ERG) were respectively used to verify cellular senescence, the structure and function of the retina. Our findings demonstrated that MSCs-EXOs inhibited HG-induced senescence in ARPE-19 cells. Furthermore, MSCs-EXOs reduced HG-induced cell apoptosis and oxidative stress levels while promoting cell proliferation. Mechanistically, HG suppressed PI3K/AKT phosphorylation as well as nuclear factor erythroid 2-related factor 2 (Nrf2) expression along with its downstream target gene expression in ARPE-19 cells. However, MSCs-EXOs reversed these changes by alleviating cellular senescence while enhancing antioxidant activity. In line with our results in vitro, MSCs-EXOs significantly ameliorated hyperglycemia-induced senescence in DR mice by downregulating mRNA expression of P53, P21, P16, and SASP. Additionally, MSCs-EXOs improved the functional and structural integrity of the retina in DR mice. Our study revealed the protective effect of MSCs-EXOs on cellular senescence, offering new insights for the treatment of DR.