Liu Jiwen, Jiang Mei, Deng Shengqiong, Lu Jide, Huang Hui, Zhang Yu, Gong Peihua, Shen Xumin, Ruan Huanjun, Jin Mingming, Wang Hairong
Department of Cardiology, Shanghai Gongli Hospital, The Second Military Medical University, Shanghai 200135, China.
Department of Neurology, Shanghai Gongli Hospital, The Second Military Medical University, Shanghai 200135, China.
Mol Ther Nucleic Acids. 2018 Jun 1;11:103-115. doi: 10.1016/j.omtn.2018.01.010. Epub 2018 Jan 31.
Adipose-derived stromal cells (ADSCs) have been considered as an attractive therapeutic tool. Accumulating evidence indicates that the healing effects of ADSCs are mainly related to paracrine action rather than transdifferentiation. Data show that the expression of miR-93-5p has a cardio-protective effect after acute myocardial infarction (AMI). To identify whether miR-93-5p-encapsulating exosomes that form ADSCs have a better cardio-protective effect, we investigated the inflammatory factors and miR-30d-5p expression in clinical levels. A rat model of AMI and an in vitro model of hypoxic H9c2 cells were established to study the protective mechanism of miR-93-5p in ischemia-induced cardiac injury. The results show that the expression of inflammatory cytokines and miR-93-5p were increased following AMI in both patients and animal models. Moreover, treatment with ADSC-derived miR-93-5p-containing exosomes has a greater protective effect on infarction-induced myocardial damage than simple exosome processing. Furthermore, in vitro experiments confirmed that the expression of miR-93-5p can significantly suppress hypoxia-induced autophagy and inflammatory cytokine expression by targeting Atg7 and Toll-like receptor 4 (TLR4), respectively, and was confirmed with Atg7 or TLR4 overexpression. The results also show that autophagy activation can promote inflammatory cytokine expression indirectly. Taken together, these results suggest that the miR-93-5p-enhanced ADSC-derived exosomes prevent cardiac injury by inhibiting autophagy and the inflammatory response.
脂肪来源的间充质干细胞（ADSCs）被认为是一种有吸引力的治疗工具。越来越多的证据表明，ADSCs的愈合作用主要与旁分泌作用有关，而非转分化。数据显示，miR-93-5p的表达在急性心肌梗死（AMI）后具有心脏保护作用。为了确定形成ADSCs的包裹miR-93-5p的外泌体是否具有更好的心脏保护作用，我们在临床水平上研究了炎症因子和miR-30d-5p的表达。建立了AMI大鼠模型和缺氧H9c2细胞的体外模型，以研究miR-93-5p在缺血性心脏损伤中的保护机制。结果表明，在患者和动物模型中，AMI后炎症细胞因子和miR-93-5p的表达均增加。此外，用ADSC来源的含miR-93-5p的外泌体治疗对梗死诱导的心肌损伤具有比单纯外泌体处理更大的保护作用。此外，体外实验证实，miR-93-5p的表达可分别通过靶向Atg7和Toll样受体4（TLR4）显著抑制缺氧诱导的自噬和炎症细胞因子表达，并通过Atg7或TLR4过表达得到证实。结果还表明，自噬激活可间接促进炎症细胞因子表达。综上所述，这些结果表明，miR-93-5p增强的ADSC来源的外泌体通过抑制自噬和炎症反应来预防心脏损伤。
