Therapeutic delivery of microRNA-125a-5p oligonucleotides improves recovery from myocardial ischemia/reperfusion injury in mice and swine.
Therapeutic delivery of microRNA-125a-5p oligonucleotides improves recovery from myocardial ischemia/reperfusion injury in mice and swine.
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microRNA-125a-5p 寡核苷酸的治疗性递送可改善小鼠和猪心肌缺血/再灌注损伤的恢复
DOI：
10.7150/thno.73568
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发表时间：
2023
期刊：
影响因子：
12.4
通讯作者：
Liu, Zhongmin
中科院分区：
文献类型：
--
作者：
Gao, Ling;Qiu, Fan;Cao, Hao;Li, Hao;Dai, Gonghua;Ma, Teng;Gong, Yanshan;Luo, Wei;Zhu, Dongling;Qiu, Zhixuan;Zhu, Ping;Chu, Shuguang;Yang, Huangtian;Liu, Zhongmin
基本原理：间充质干细胞（MSC）和MSC衍生的外泌体（MSC-Exos）用于减轻心肌缺血/再灌注（I/R）损伤的临床应用受到低细胞植入率和不受控制的外泌体含量的影响。作为其活性成分之一，单组分microRNA疗法可能具有更多的先天优势。我们试图找到一种理想的microRNA候选物，并确定它是否可以重现MSC和MSC-Exos的心脏保护作用。研究方法：在I/R损伤后，研究了MSC、MSC-Exo或microRNA阿托伐他汀处理的小鼠心脏的心功能和心肌重塑。microRNA寡核苷酸对心脏细胞（巨噬细胞、心肌细胞、成纤维细胞和内皮细胞）的作用及其下游机制得到证实。大型动物也被用来研究microRNA治疗的安全性。结果如下：结果表明，microRNA-125 a-5 p（miR-125 a-5 p）在MSC-Exos中富集，其修饰的寡核苷酸（agomir）在小鼠I/R心肌中的心肌内递送以及MSC或MSC-Exos通过增加心脏功能和限制不良重构而发挥明显的心脏保护作用。此外，miR-125 a-5 p阿戈米尔治疗增加了M2巨噬细胞极化，促进了血管生成，并减弱了成纤维细胞增殖和活化，从而有助于改善心肌细胞凋亡和炎症。从机制上讲，Klf 13、Tgfbr 1和Daam 1被认为是miR-125 a-5 p分别调节巨噬细胞、成纤维细胞和内皮细胞功能的靶点。在猪模型中，miR-125 a-5 p阿戈米尔治疗后观察到类似的结果，心律失常或肝、肾或心脏毒性的风险未增加。结论：这种靶向microRNA递送作为I/R心脏修复中的干细胞和外泌体治疗提供了一种有效且安全的策略。
Rationale: Clinical application of mesenchymal stem cells (MSCs) and MSC-derived exosomes (MSC-Exos) to alleviate myocardial ischemia/reperfusion (I/R) injury is compromised by the low cell engraftment rate and uncontrolled exosomal content. As one of their active ingredients, single-component microRNA therapy may have more inherent advantages. We sought to find an ideal microRNA candidate and determine whether it could reproduce the cardioprotective effects of MSCs and MSC-Exos. Methods: Cardiac function and myocardial remodeling in MSC, MSC-Exo, or microRNA oligonucleotide-treated mouse hearts were investigated after I/R injury. The effects of microRNA oligonucleotides on cardiac cells (macrophages, cardiomyocytes, fibroblasts, and endothelial cells) and their downstream mechanisms were confirmed. Large animals were also employed to investigate the safety of microRNA therapy. Results: The results showed that microRNA-125a-5p (miR-125a-5p) is enriched in MSC-Exos, and intramyocardial delivery of their modified oligonucleotides (agomir) in mouse I/R myocardium, as well as MSCs or MSC-Exos, exerted obvious cardioprotection by increasing cardiac function and limiting adverse remodeling. In addition, miR-125a-5p agomir treatment increased M2 macrophage polarization, promoted angiogenesis, and attenuated fibroblast proliferation and activation, which subsequently contributed to the improvements in cardiomyocyte apoptosis and inflammation. Mechanistically, Klf13, Tgfbr1, and Daam1 are considered the targets of miR-125a-5p for regulating the function of macrophages, fibroblasts, and endothelial cells, respectively. Similar results were observed following miR-125a-5p agomir treatment in a porcine model, with no increase in the risk of arrhythmia or hepatic, renal, or cardiac toxicity. Conclusions: This targeted microRNA delivery presents an effective and safe strategy as a stem cell and exosomal therapy in I/R cardiac repair.
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影响因子：
24
作者：
Hare, Joshua M.;Traverse, Jay H.;Henry, Timothy D.;Dib, Nabil;Strumpf, Robert K.;Schulman, Steven P.;Gerstenblith, Gary;DeMaria, Anthony N.;Denktas, Ali E.;Gammon, Roger S.;Hermiller, James B., Jr.;Reisman, Mark A.;Schaer, Gary L.;Sherman, Warren
通讯作者：
Sherman, Warren
影响因子：
12.4
作者：
Han D;Yang J;Zhang E;Liu Y;Boriboun C;Qiao A;Yu Y;Sun J;Xu S;Yang L;Yan W;Luo B;Lu D;Zhang C;Jie C;Mobley J;Zhang J;Qin G
通讯作者：
Qin G
影响因子：
12.4
作者：
Hwang, Su Jung;Ahn, Bum Ju;Shin, Min-Wook;Song, Ye-Seul;Choi, Youngbin;Oh, Goo Taeg;Kim, Kyu-Won;Lee, Hyo-Jong
通讯作者：
Lee, Hyo-Jong
影响因子：
3.6
作者：
Nernpermpisooth N;Sarre C;Barrere C;Contreras R;Luz-Crawford P;Tejedor G;Vincent A;Piot C;Kumphune S;Nargeot J;Jorgensen C;Barrère-Lemaire S;Djouad F
通讯作者：
Djouad F
DOI：
10.1073/pnas.1001075107
发表时间：
2010-04-13
影响因子：
11.1
作者：
Ju, Rong;Cirone, Pasquale;Crews, Craig M.
通讯作者：
Crews, Craig M.