源自阿片肽预处理间充质干细胞的外泌体通过递送miR-34a-5p减轻心肌细胞焦亡，改善脓毒症诱导的心肌功能障碍。
Exosomes Derived from Apelin-Pretreated Mesenchymal Stem Cells Ameliorate Sepsis-Induced Myocardial Dysfunction by Alleviating Cardiomyocyte Pyroptosis via Delivery of miR-34a-5p.
作者信息
Li Ting, Zhao Yuechu, Cao Zhi, Shen Ying, Chen Jiaqi, Huang Xinran, Shao Zhuang, Zeng Yi, Chen Qi, Yan Xiaofei, Li Xin, Zhang Yuelin, Hu Bei
机构信息
School of Medicine, South China University of Technology, Guangzhou, Guangdong, People's Republic of China.
Department of Emergency Medicine, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong, People's Republic of China.
出版信息
Int J Nanomedicine. 2025 Jan 17;20:687-703. doi: 10.2147/IJN.S498770. eCollection 2025.
BACKGROUND
Exosomes sourced from mesenchymal stem cells (MSC-EXOs) have become a promising therapeutic tool for sepsis-induced myocardial dysfunction (SMD). Our previous study demonstrated that Apelin pretreatment enhanced the therapeutic benefit of MSCs in myocardial infarction by improving their paracrine effects. This study aimed to determine whether EXOs sourced from Apelin-pretreated MSCs (Apelin-MSC-EXOs) would have potent cardioprotective effects against SMD and elucidate the underlying mechanisms.
METHODS
MSC-EXOs and Apelin-MSC-EXOs were isolated and identified. Mice neonatal cardiomyocytes (NCMs) were treated with MSC-EXOs or Apelin-MSC-EXOs under lipopolysaccharide (LPS) condition in vitro. Cardiomyocyte pyroptosis was determined by TUNEL staining. RNA sequencing was used to identify differentially expressed functional miRNAs between MSC-EXOs and Apelin-MSC-EXOs. MSC-EXOs and Apelin-MSC-EXOs were transplanted into a mouse model of SMD induced by cecal ligation puncture (CLP) via the tail vein. Heart function was evaluated by echocardiography.
RESULTS
Compared with MSC-EXOs, Apelin-MSC-EXO transplantation greatly enhanced cardiac function in SMD mice. Both MSC-EXOs and Apelin-MSC-EXOs suppressed cardiomyocyte pyroptosis in vivo and in vitro, with the latter exhibiting superior protective effects. miR-34a-5p effectively mediated Apelin-MSC-EXOs to exert their cardioprotective effects in SMD with high mobility group box-1 (HMGB1) as the potential target. Mechanistically, Apelin-MSC-EXOs delivered miR-34a-5p into injured cardiomyocytes, thereby ameliorating cardiomyocyte pyroptosis via regulation of the HMGB1/AMPK axis. These cardioprotective effects were partially abrogated by downregulation of miR-34a-5p in Apelin-MSC-EXOs.
CONCLUSION
Our study revealed miR-34a-5p as a key component of Apelin-MSC-EXOs that protected against SMD via mediation of the HMGB1/AMPK signaling pathway.
背景
间充质干细胞来源的外泌体（MSC-EXOs）已成为脓毒症诱导的心肌功能障碍（SMD）的一种有前景的治疗工具。我们之前的研究表明，Apelin预处理通过改善间充质干细胞的旁分泌作用增强了其对心肌梗死的治疗效果。本研究旨在确定Apelin预处理的间充质干细胞来源的外泌体（Apelin-MSC-EXOs）是否对SMD具有强大的心脏保护作用，并阐明其潜在机制。
方法
分离并鉴定MSC-EXOs和Apelin-MSC-EXOs。在体外脂多糖（LPS）条件下，用MSC-EXOs或Apelin-MSC-EXOs处理小鼠原代心肌细胞（NCMs）。通过TUNEL染色确定心肌细胞焦亡情况。RNA测序用于鉴定MSC-EXOs和Apelin-MSC-EXOs之间差异表达的功能性miRNA。将MSC-EXOs和Apelin-MSC-EXOs通过尾静脉移植到盲肠结扎穿刺（CLP）诱导的SMD小鼠模型中。通过超声心动图评估心脏功能。
结果
与MSC-EXOs相比，Apelin-MSC-EXO移植显著增强了SMD小鼠的心脏功能。MSC-EXOs和Apelin-MSC-EXOs在体内和体外均抑制心肌细胞焦亡，后者表现出更强的保护作用。miR-34a-5p有效地介导Apelin-MSC-EXOs在SMD中发挥心脏保护作用，以高迁移率族蛋白B1（HMGB1）作为潜在靶点。机制上，Apelin-MSC-EXOs将miR-34a-5p递送至受损心肌细胞，从而通过调节HMGB1/AMPK轴改善心肌细胞焦亡。Apelin-MSC-EXOs中miR-34a-5p的下调部分消除了这些心脏保护作用。
结论
我们的研究揭示miR-34a-5p是Apelin-MSC-EXOs的关键组成部分，其通过介导HMGB1/AMPK信号通路对SMD具有保护作用。
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