Duan Tian-Qi, Gao Zhao-Lin, Luo Ai-Xiang, Chen Dan, Tong Jian-Bin, Huang Ju-Fang
Department of Anatomy and Neurobiology, School of Basic Medical Sciences, Central South University, Changsha, Hunan Province, China.
Hunan Province Key Laboratory of Brain Homeostasis, Third Xiangya Hospital, Central South University, Changsha, Hunan Province, China.
Neural Regen Res. 2023 Oct;18(10):2315-2320. doi: 10.4103/1673-5374.369123.
Adipose mesenchymal stem cells (ADSCs) have protective effects against glutamate-induced excitotoxicity, but ADSCs are limited in use for treatment of optic nerve injury. Studies have shown that the extracellular vesicles (EVs) secreted by ADSCs (ADSC-EVs) not only have the function of ADSCs, but also have unique advantages including non-immunogenicity, low probability of abnormal growth, and easy access to target cells. In the present study, we showed that intravitreal injection of ADSC-EVs substantially reduced glutamate-induced damage to retinal morphology and electroretinography. In addition, R28 cell pretreatment with ADSC-EVs before injury inhibited glutamate-induced overload of intracellular calcium, downregulation of α-amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid receptor (AMPAR) subunit GluA2, and phosphorylation of GluA2 and protein kinase C alpha in vitro. A protein kinase C alpha agonist, 12-O-tetradecanoylphorbol 13-acetate, inhibited the neuroprotective effects of ADSC-EVs on glutamate-induced R28 cells. These findings suggest that ADSC-EVs ameliorate glutamate-induced excitotoxicity in the retina through inhibiting protein kinase C alpha activation.
脂肪间充质干细胞（ADSCs）对谷氨酸诱导的兴奋性毒性具有保护作用，但ADSCs在视神经损伤治疗中的应用受到限制。研究表明，ADSCs分泌的细胞外囊泡（EVs，即ADSC-EVs）不仅具有ADSCs的功能，还具有独特优势，包括无免疫原性、异常生长概率低以及易于作用于靶细胞。在本研究中，我们发现玻璃体内注射ADSC-EVs可显著减轻谷氨酸诱导的视网膜形态损伤和视网膜电图改变。此外，在损伤前用ADSC-EVs预处理R28细胞可在体外抑制谷氨酸诱导的细胞内钙超载、α-氨基-3-羟基-5-甲基-4-异恶唑丙酸受体（AMPAR）亚基GluA2的下调以及GluA2和蛋白激酶Cα的磷酸化。蛋白激酶Cα激动剂12-O-十四酰佛波醇-13-乙酸酯可抑制ADSC-EVs对谷氨酸诱导的R28细胞的神经保护作用。这些发现表明，ADSC-EVs通过抑制蛋白激酶Cα的激活来改善谷氨酸诱导的视网膜兴奋性毒性。
