Enhanced Therapeutic Effects of Extracellular Vesicles Targeting MiR-137 Contribute to Functional Recovery by Attenuating Neuronal Injury After Ischemic Stroke
Hui‑Xin Zhang1 · Li‑Qing Tao1 · Yi‑Hang Chen1 · Tian‑Yi Jiang1 · Zhi‑Yuan Ye1 · Wen She1,4 · Chang‑Ying Chen3 · Ya‑Li Han2 · Cui Qi1 · Chong Shen3 · Jun Gao1,2
1 Department of Neurobiology, School of Basic Medical Science, Nanjing Medical University, Nanjing 211166, China
2 Shanghai Key Laboratory of Craniomaxillofacial Development and Diseases, Stomatological Institute of Integrated Innovation, Shanghai Stomatological Hospital & School of Stomatology, Fudan University, Room 719, No. 166, Hechuan Road, Minhang District, Shanghai 200001, China
3 Department of Epidemiology, School of Public Health, Nanjing Medical University, Nanjing 211166, China
4 Nantong Fourth People’s Hospital, Nantong 226005, China
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
Extracellular vesicles; miR-137; Sirtuin1; Ischemia; Maged1
