Exosomes from adipose-derived stem cells alleviate myocardial infarction via microRNA-31/FIH1/HIF-1α pathway.
Exosomes from adipose-derived stem cells alleviate myocardial infarction via microRNA-31/FIH1/HIF-1α pathway.
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DOI：
10.1016/j.yjmcc.2021.08.010
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发表时间：
2022-01
影响因子：
5
通讯作者：
Liu D
中科院分区：
文献类型：
--
作者：
Zhu D;Wang Y;Thomas M;McLaughlin K;Oguljahan B;Henderson J;Yang Q;Chen YE;Liu D
我们之前的研究表明，来自脂肪源性干细胞（ASCs）的外泌体通过递送靶向受体细胞中抑制缺氧诱导因子-1 （FIH1）的microRNA-31 (miR-31)，促进皮下移植凝胶中的血管生成。在这里，我们假设ASC外泌体通过miR-31/FIH1/缺氧诱导因子-1α (HIF-1α)信号通路缓解缺血性疾病。利用纳米颗粒跟踪分析、透射电镜和免疫印迹分析对ASCs外泌体进行表征。缺血小鼠后肢的免疫印迹和激光成像结果显示，miR-31富集的ASC外泌体分别抑制了FIH1的表达，增强了血液灌注。当使用mir -31缺失的外泌体时，这些效应被削弱。免疫组织化学分析显示，与mir -31缺失外泌体相比，外泌体的使用导致缺血后肢的小动脉密度更高，CD31+面积更大。同样，外泌体中miR-31的敲低降低了外泌体增加心室分数缩短和CD31+面积以及减少梗死面积的作用。外泌体促进内皮细胞迁移和小管形成。当外泌体中miR-31缺失或内皮细胞中FIH1过表达时，这些变化减弱。此外，免疫细胞化学、共免疫沉淀和荧光素酶报告分析的结果表明，当miR-31在外泌体中缺失或FIH1过表达时，外泌体对核易位、与共激活因子p300结合以及HIF-1α活化的影响减弱。我们的研究结果提供了证据，表明ASCs外泌体通过转运miR-31促进小鼠缺血后肢和心脏的血管生成，miR-31靶向FIH1，从而触发HIF-1α转录激活。
Our previous study has revealed that exosomes from adipose-derived stem cells (ASCs) promote angiogenesis in subcutaneously transplanted gels by delivery of microRNA-31 (miR-31) which targets factor inhibiting hypoxia-inducible factor-1 (FIH1) in recipient cells. Here we hypothesized that ASC exosomes alleviate ischemic diseases through miR-31/FIH1/hypoxia-inducible factor-1α (HIF-1α) signaling pathway. Exosomes from ASCs were characterized with nanoparticle tracking analysis, transmission electron microscopy, and immunoblotting analysis for exosomal markers. Results from immunoblotting and laser imaging of ischemic mouse hindlimb revealed that miR-31 enriched ASC exosomes inhibited FIH1 expression and enhanced the blood perfusion, respectively. These effects were impaired when using miR-31-depleted exosomes. Immunohistochemistry analysis showed that administration of exosomes resulted in a higher arteriole density and larger CD31+ area in ischemic hindlimb than miR-31-delpleted exosomes. Similarly, knockdown of miR-31 in exosomes reduced the effects of the exosomes on increasing ventricular fraction shortening and CD31+ area, and on decreasing infarct size. Exosomes promoted endothelial cell migration and tube formation. These changes were attenuated when miR-31 was depleted in the exosomes or when FIH1 was overexpressed in the endothelial cells. Furthermore, the results from immunocytochemistry, co-immunoprecipitation, and luciferase reporter assay demonstrated that the effects of exosomes on nuclear translocation, binding with co-activator p300, and activation of HIF-1α were decreased when miR-31 was depleted in the exosomes or FIH1 was overexpressed. Our findings provide evidence that exosomes from ASCs promote angiogenesis in both mouse ischemic hindlimb and heart through transport of miR-31 which targets FIH1 and therefore triggers HIF-1α transcriptional activation.
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DOI：
10.1126/science.aau6977
发表时间：
2020-02-07
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Kalluri R;LeBleu VS
通讯作者：
LeBleu VS
DOI：
10.1016/j.apsb.2016.02.001
发表时间：
2016-07
期刊：
Acta pharmaceutica Sinica. B
影响因子：
--
作者：
Ha D;Yang N;Nadithe V
通讯作者：
Nadithe V
影响因子：
--
作者：
Luo, Qiancheng;Guo, Dongfeng;Jin, Mingming
通讯作者：
Jin, Mingming
影响因子：
6
作者：
Kang T;Jones TM;Naddell C;Bacanamwo M;Calvert JW;Thompson WE;Bond VC;Chen YE;Liu D
通讯作者：
Liu D
影响因子：
20.1
作者：
Bishop T;Ratcliffe PJ
通讯作者：
Ratcliffe PJ