【科技前瞻】 J Clin Invest：最新研究揭秘外泌体再生修复能力的分子机制

生物_医药_科研 2019-07-16

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细胞疗法对受损的心肌再生具有潜在作用，心肌再生的细胞疗法具有绝对安全性，只显示非边缘效应。无细胞和无生命治疗物的开发具有革新心血管再生医学的潜力。无细胞疗法可以通过旁分泌机制影响干细胞的分化，而不需要直接注射干细胞使其分化为心肌细胞。因此，无细胞疗法的作用机制研究显得尤为重要，近日，研究人员揭秘了心力衰竭患者的心脏基质细胞来源的外泌体的再生修复作用发生障碍的具体机制，相关研究结果发表在Journal of clinical investigation杂志上。

外泌体作为细胞治疗的功能性旁分泌单位，可以部分复制其亲代细胞的修复特性。外泌体的构成及其生物活性在很大程度上取决于其来源细胞。研究人员从心力衰竭患者(FEXO)或正常供体心脏(NEXO)的心脏基质细胞中分离外泌体，并比较它们在体外和体内的再生修复活性。体外研究结果显示FEXO组患者心脏来源的外泌体内皮细胞形成和心肌细胞增殖的能力受损。心肌内注射NEXO改善了小鼠急性心肌梗死模型的结构和功能。相反，FEXO疗法加剧了心脏功能和左心室重构。micoRNA序列分析和PCR分析结果显示，FEXO源外泌体中的miR-21-5p表达失调。恢复miR-21-5p表达可重塑FEXO源外泌体的修复功能，而抑制NEXO中miR-21-5p的表达可显著降低其外泌体的再生修复治疗效果。进一步的机理研究显示，miR-21-5p通过抑制磷酸酶和tensin同源物从而增强Akt激酶活性。综上，该研究结果提示心力衰竭病理状态改变了心脏来源的外泌体的组分从而损害了其再生修复能力，外泌体中的miR-21-5p表达可有效促进血管生成和心肌细胞存活，从而有助于心脏修复。

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microRNA-21-5p dysregulation in exosomes derived from heart failure patients impairs regenerative potential.

Exosomes, as functional paracrine units of therapeutic cells, can partially reproduce the reparative properties of their parental cells. The constitution of exosomes, as well as their biological activity, largely depends on the cells that secrete them. We isolated exosomes from explant-derived cardiac stromal cells from patients with heart failure (FEXO) or from normal donor hearts (NEXO) and compared their regenerative activities in vitro and in vivo. Patients in the FEXO group exhibited an impaired ability to promote endothelial tube formation and cardiomyocyte proliferation in vitro. Intramyocardial injection of NEXO resulted in structural and functional improvements in a murine model of acute myocardial infarction. In contrast, FEXO therapy exacerbated cardiac function and left ventricular remodeling. microRNA array and PCR analysis revealed dysregulation of miR-21-5p in FEXO. Restoring miR-21-5p expression rescued FEXO's reparative function, whereas blunting miR-21-5p expression in NEXO diminished its therapeutic benefits. Further mechanistic studies revealed that miR-21-5p augmented Akt kinase activity through the inhibition of phosphatase and tensin homolog. Taken together, the heart failure pathological condition altered the miR cargos of cardiac-derived exosomes and impaired their regenerative activities. miR-21-5p contributes to exosome-mediated heart repair by enhancing angiogenesis and cardiomyocyte survival through the phosphatase and tensin homolog/Akt pathway.