Mesenchymal stem cell-derived exosomal miR-143-3p suppresses myocardial ischemia-reperfusion injury by regulating autophagy
Mesenchymal stem cell-derived exosomal miR-143-3p suppresses myocardial ischemia-reperfusion injury by regulating autophagy
复制标题
间充质干细胞来源的胞外体miR-143-3p通过调节自噬抑制心肌缺血再灌注损伤
DOI：
10.1016/j.lfs.2021.119742
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发表时间：
2021-06-24
期刊：
影响因子：
6.1
通讯作者：
Tang, Chengchun
中科院分区：
文献类型：
--
作者：
Chen, Gecai;Wang, Meixiang;Tang, Chengchun
目的：心肌缺血-再灌注（I/R）损伤被认为是心肌灌注挽救急性心肌梗死的主要障碍，严重威胁着人类的健康。大量证据表明，间充质干细胞（MSCs）作为成体干细胞在受损心肌的再生和修复中发挥着重要作用。然而，MSC衍生的外泌体在心肌I/R损伤保护中的生物学作用尚未阐明。主要方法：本研究从大鼠股骨和胫骨骨髓中分离、培养和鉴定骨髓间充质干细胞。以H9 c2细胞建立细胞缺氧-复氧（H/R）模型，并与MSCs及MSCs来源的exosomes共培养。关键发现：功能实验表明，MSC和MSC衍生的外泌体抑制H/R诱导的细胞凋亡和细胞自噬。有趣的是，雷帕霉素作为自噬激活剂逆转了MSC来源的exosomes的积极作用，而3-甲基腺嘌呤（3-MA）作为自噬抑制剂进一步促进了MSC来源的exosomes的作用，表明MSC通过介导自噬发挥其在H/R损伤中的作用。随后，我们发现CHK 2-Beclin 2通路参与了H/R诱导的自噬。在机制上，miR 143 - 3 p直接靶向CHK 2并负调节CHK 2表达。此外，外泌体miR-143- 3 p的抑制通过CHK 2-Beclin 2途径促进H/R诱导的自噬。与体外实验的结果一致，体内实验证实了外泌体miR-143- 3 p通过CHK 2-Beclin 2途径调节自噬而有效减少细胞凋亡。重要性：总的来说，我们的研究结果表明，MSC衍生的外泌体miR-143- 3 p可能代表了治疗I/R损伤的有希望的选择。
Aims: Myocardial ischemia-reperfusion (I/R) injury is considered as a major obstacle of myocardial perfusion to save acute myocardial infarction, and causes a serious threat to human health. An extensive body of evidence has unveiled that mesenchymal stem cells (MSCs) as adult stem cells play a vital role in the field of damaged myocardial regeneration and repair. However, the biological role of MSCs derived-exosomes in the protection of myocardial I/R injury has not been elucidated. Main methods: In this study, we isolated and characterized MSCs from the bone marrow of rats femur and tibia. H9c2 cells were administrated to established the cellular hypoxia-reoxygenation (H/R) model, and co-cultured with MSCs and MSCs-derived exosomes. Key findings: Functional experiments revealed that MSCs and MSCs-derived exosomes inhibited H/R-induced cell apoptosis and cell autophagy. Interestingly, rapamycin as an activator of autophagy reversed the positive effects of MSCs-derived exosomes, while 3-methyladenine (3-MA) as autophagy inhibitor further promoted the effects of MSCs-derived exosomes, indicating MSCs exerted its function on H/R injury by mediating autophagy. Subsequently, we found that CHK2-Beclin2 pathway participated in H/R-induced autophagy. Mechanistically, miR143-3p directly targeted CHK2 and negatively regulated CHK2 expression. Moreover, repression of exosomal miR-143-3p promoted H/R-induced autophagy via CHK2-Beclin2 pathway. Consistent with the results of in vitro experiments, in vivo experiments confirmed that exosomal miR-143-3p effectively reduced cell apoptosis by regulating autophagy via CHK2-Beclin2 pathway. Significance: Collectively, our results indicated that MSCs-derived exosomal miR-143-3p might represent a promising option for the treatment of I/R injury.