Enhanced Therapeutic Effects of Extracellular Vesicles Targeting MiR-137 Contribute to Functional Recovery by Attenuating Neuronal Injury After Ischemic Stroke

Abstract

Ischemic stroke is a leading cause of death, especially among aging populations. MicroRNA-137 (miR-137) is known to be involved in neurodevelopment. However, its role in ischemic stroke is still unexplored. Here, we assessed the regulation of miR-137 after cerebral ischemia and reperfusion (I/R) and developed a targeted delivery therapy by extracellular vesicles (EVs). Our results showed that miR-137 was enhanced in the hippocampus of mice after I/R. miR-137 regulated the ischemia-induced cell death by decreasing the expression of Sirtuin1 (Sirt1). Therefore, we evaluated a therapeutic approach involving mesenchymal stem cell-derived EVs. Systemic delivery of anti-miR-137 by rabies virus glycoprotein-modified EVs allowed specific targeting of neurons. After anti-miR-137 treatment, the survival rate was increased in ischemic mice, and some neurobehavioral deficits were alleviated. We also established that Maged1 deficiency attenuated ischemic damage and inhibited miR-137 enrichment. Besides, the increase of miR-137 increased neuronal death and neurological deficits after I/R through the MAGED1/miR-137/Sirt1 pathway. Combined with rabies virus glycoprotein-modified EVs and anti-miR-137, this is a new strategy for regulating ischemic neuronal injury and functional recovery by targeting miR-137.

Keywords: Maged1; Extracellular vesicles; Ischemia; Sirtuin1; miR-137.