Down-Regulated Exosomal MicroRNA-221-3p Derived From Senescent Mesenchymal Stem Cells Impairs Heart Repair
Down-Regulated Exosomal MicroRNA-221-3p Derived From Senescent Mesenchymal Stem Cells Impairs Heart Repair
复制标题
来自衰老间充质干细胞的下调外泌体 MicroRNA-221 – 3p 会损害心脏修复
DOI：
10.3389/fcell.2020.00263
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发表时间：
2020-05-05
影响因子：
5.5
通讯作者：
Zhang, Fengxiang
中科院分区：
文献类型：
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作者：
Sun, Ling;Zhu, Wenwu;Zhang, Fengxiang
供体细胞的组成和生物活性在很大程度上取决于它们分泌的外泌体。在这项研究中，我们从年轻的（Young-Exo）和老年的（EST-Exo）间充质干细胞（MSC）中分离出外泌体，并比较了它们的再生活性。年轻的Exo MSCs在体外促进内皮管形成、减少纤维化和抑制心肌细胞凋亡方面比成熟的Exo更有效;在心肌梗死（MI）后的大鼠心脏中，在体内改善心脏结构和功能。microRNA测序和聚合酶链反应（PCR）分析显示miR-221- 3 p在pMD-Exo中显著下调。当miR-221- 3 p在pMD-Exo中过表达时，老化的MSC被返老还童并且其修复心脏的能力被恢复。当Young-Exo中miR-221- 3 p表达被敲低时，保护作用丧失。miR-221- 3 p的这些作用通过抑制磷酸酶和张力蛋白同源物（PTEN）增强Akt激酶活性来实现。结论：衰老MSCs分泌的外泌体miR-221- 3 p可抑制心肌细胞的血管生成，促进心肌细胞的存活。上调miR-221- 3 p可增强衰老MSCs的血管生成、迁移和增殖能力，并通过PTEN/Akt途径抑制凋亡。
The composition and biological activity of donor cells is largely determined by the exosomes they secrete. In this study, we isolated exosomes from young (Young-Exo) and aged (Age-Exo) mesenchymal stem cells (MSCs) and compared their regeneration activity. Young Exo MSCs were more efficient than Aged-Exo at promoting the formation of endothelial tube, reducing fibrosis, and inhibiting apoptosis of cardiomyocytes in vitro; and improving cardiac structure and function in vivo in the hearts of rats following myocardial infarction (MI). MicroRNA sequencing and polymerase chain reaction (PCR) analysis revealed that miR-221-3p was significantly down-regulated in Aged-Exo. The aged MSCs were rejuvenated and their reparative cardiac ability restored when miR-221-3p was overexpressed in Aged-Exo. The protective effect was lost when miR-221-3p expression was knocked down in Young-Exo. These effects of miR-221-3p were achieved through enhancing Akt kinase activity by inhibiting phosphatase and tensin homolog (PTEN). In conclusion, exosomal miR-221-3p secreted from Aged MSCs attenuated the function of angiogenesis and promoted survival of cardiomyocytes. Up-regulation of miR-221-3p in aged MSCs improved their ability of angiogenesis, migration and proliferation, and suppressed apoptosis via the PTEN/Akt pathway.