Exosomal miR-146a derived from human umbilical cord mesenchymal stem cells alleviates inflammation and apoptosis in dry eye disease by targeting SQSTM1.

Dry eye disease negatively impacts the quality of life of many patients worldwide, and currently, there is no cure. Stem cell therapy may offer a potential new treatment option. Mesenchymal stem cells (MSCs)-derived exosomes have similar effects as MSCs but with fewer side effects. This study investigated the effects and mechanisms of human umbilical cord mesenchymal stem cells (HUCMSCs)-derived exosomes in cell and mouse models of dry eye disease. Exosomes were isolated from HUCMSCs (HUCMSCs-EXO) and characterized by measuring surface markers. Human corneal epithelial cells (HCECs) were cultured in hypertonic (500 mOsm) or isotonic medium (310 mOsm) and treated with HUCMSC-EXO or PBS. A mouse model of dry eye disease was generated by treating mice with benzalkonium chloride and confirmed by measuring tear secretion and performing H&E staining. Cell viability, apoptosis, RNA, and protein expression levels were assessed using CCK-8 assay, TUNEL staining, qPCR, and Western blotting. The regulation of SQSTM1 expression by miR-146a was evaluated using a dual luciferase reporting assay. Exposure to hyperosmotic pressure decreased cell viability, increased apoptosis and inflammation, decreased miR-146a expression, and increased SQSTM1 expression in HCECs. Treatment with HUCMSCs-EXO alleviated the effects of hyperosmotic pressure on inflammation and apoptosis. Overexpression of miR-146a increased cell viability and inhibited apoptosis and inflammation, suggesting that miR-146a mediates the beneficial effects of HUCMSCs-EXO. These findings were validated in the mouse model of dry eye disease. Further experiments revealed that miR-146a targets and promotes SQSTM1 expression. Overexpression of SQSTM1 increased cell viability and inhibited apoptosis and inflammation in HCECs. In conclusion, this study demonstrated that HUCMSCs-derived exosomal miR-146a targets SQSTM1 and promotes its expression, resulting in the alleviation of inflammation and apoptosis in cell and mouse models of dry eye disease.