School of Medicine, Jiangsu University, Zhenjiang, Jiangsu 212013, P.R. China.
Department of Clinical Laboratory, Zhenjiang Provincial Blood Center, Zhenjiang, Jiangsu 212000, P.R. China.
Int J Mol Med. 2018 May;41(5):3063-3072. doi: 10.3892/ijmm.2018.3496. Epub 2018 Feb 16.
It has been previously reported that exosomes derived from human umbilical cord mesenchymal stem cells (hucMSC)‑exosomes exhibit cardioprotective effects on the rat acute myocardial infarction (AMI) models and cardiomyocyte hypoxia injury models in vitro, however the exact mechanisms involved require further investigation. The present study aimed to investigate the repair effects of hucMSC‑exosomes on myocardial injury via the regulation of mothers against decapentaplegic homolog 7 (Smad7) expression. Compared with sham or normoxia groups (in vivo and in vitro, respectively), western blotting demonstrated that Smad7 expression was significantly decreased in the borderline area of infraction myocardium and in H9C2(2‑1) cells following hypoxia‑induced injury. Additionally, microRNA (miR)‑125b‑5p expression was markedly increased using reverse transcription‑quantitative polymerase chain reaction, but was reversed by hucMSC‑exosomes. Trypan blue staining and lactate dehydrogenase release detection demonstrated that cell injury was significantly increased in the AMI + PBS and hypoxia group compared with in the sham and normoxia groups and was inhibited by hucMSC‑exosomes. A dual luciferase reporter gene assay confirmed that Smad7 is a target gene of miR‑125b‑5p. In addition, miR‑125b‑5p mimics promoted H9C2(2‑1) cell injury following 48 h exposure to hypoxia. Downregulation of Smad7 expression under hypoxia was increased by miR‑125b‑5p mimics compared with the mimic negative control, and hucMSC‑exosomes partially alleviated this phenomenon. In conclusion, hucMSC‑exosomes may promote Smad7 expression by inhibiting miR‑125b‑5p to increase myocardial repair. The present study may provide a potential therapeutic approach to improve myocardial repair following AMI.
先前有报道称，人脐带间充质干细胞（hucMSC）衍生的外泌体对大鼠急性心肌梗死（AMI）模型和体外心肌细胞缺氧损伤模型具有心脏保护作用，但其具体作用机制仍需进一步研究。本研究旨在通过调节母系对抗 dpp 同源物 7（Smad7）表达，探讨 hucMSC 外泌体对心肌损伤的修复作用。与假手术或常氧组（体内和体外）相比，Western blot 检测结果表明，缺氧诱导损伤后，梗死边缘区心肌和 H9C2（2-1）细胞中 Smad7 表达明显下调。此外，逆转录定量聚合酶链反应显示微小 RNA（miR）-125b-5p 的表达显著增加，但被 hucMSC 外泌体逆转。台盼蓝染色和乳酸脱氢酶释放检测结果表明，与假手术和常氧组相比，AMI+PBS 和缺氧组的细胞损伤明显增加，而 hucMSC 外泌体则抑制了细胞损伤。双荧光素酶报告基因检测证实 Smad7 是 miR-125b-5p 的靶基因。此外，miR-125b-5p 模拟物在暴露于缺氧 48 h 后促进了 H9C2（2-1）细胞损伤。与模拟物阴性对照相比，缺氧下 Smad7 表达的下调在 miR-125b-5p 模拟物的作用下增加，而 hucMSC 外泌体部分缓解了这种现象。综上所述，hucMSC 外泌体可能通过抑制 miR-125b-5p 来增加 Smad7 表达，从而促进心肌修复。本研究可能为改善 AMI 后心肌修复提供一种潜在的治疗方法。
