Enhanced Cardioprotection by Human Endometrium Mesenchymal Stem Cells Driven by Exosomal MicroRNA-21.
Enhanced Cardioprotection by Human Endometrium Mesenchymal Stem Cells Driven by Exosomal MicroRNA-21.
复制标题
外泌体 MicroRNA-21 驱动的人子宫内膜间充质干细胞增强心脏保护作用
DOI：
10.5966/sctm.2015-0386
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发表时间：
2017-01
影响因子：
6
通讯作者：
Wang J
中科院分区：
文献类型：
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作者：
Wang K;Jiang Z;Webster KA;Chen J;Hu H;Zhou Y;Zhao J;Wang L;Wang Y;Zhong Z;Ni C;Li Q;Xiang C;Zhang L;Wu R;Zhu W;Yu H;Hu X;Wang J
我们的小组最近报道了将人子宫内膜来源的间充质干细胞（EnMSC）递送到梗死大鼠心肌的积极治疗益处，与人骨髓MSC（BMMSCs）的平行培养物相比，这种作用与保护性细胞因子和生长因子的分泌增强相关。为了更精确地定义EnMSC治疗的分子机制，在本研究中，我们平行评估了心肌梗死（MI）大鼠模型中来自子宫内膜、骨髓和脂肪组织的MSC的旁分泌和治疗特性。通过荧光激活细胞分选（FACS）表征EnMSC、BMMSC和脂肪来源的MSC（AdMSC）。通过与新生心肌细胞和人脐静脉内皮细胞共培养，在体外评估旁分泌和细胞保护作用。采用大鼠心肌梗死模型比较心肌内注射BMMSCs、AdMSCs和EnMSCs的细胞治疗。我们发现，EnMSCs赋予上级心脏保护相对于BMMSCs或AdMSCs和支持增强微血管密度。抑制剂研究表明，增强的旁分泌作用的EnMSCs介导的分泌外泌体。通过miR阵列和定量聚合酶链反应分析外泌体microRNA（miR），揭示了miR-21在来源于EnMSC的外泌体中的表达选择性增强。通过抗miR处理对miR-21的选择性拮抗作用消除了EnMSC的抗凋亡和血管生成作用，同时对磷酸酶和张力蛋白同源物（PTEN）、miR-21靶点和下游Akt产生平行作用。本研究的结果证实了EnMSC相对于BMMSC或AdMSC具有更好的上级心脏保护作用，并暗示miR-21通过PTEN/Akt途径增强细胞存活，作为EnMSC治疗的潜在介导剂。子宫内膜可能是心血管细胞治疗的首选MSCs来源。干细胞转化医学2017;6：209-222
Our group recently reported positive therapeutic benefit of human endometrium‐derived mesenchymal stem cells (EnMSCs) delivered to infarcted rat myocardium, an effect that correlated with enhanced secretion of protective cytokines and growth factors compared with parallel cultures of human bone marrow MSCs (BMMSCs). To define more precisely the molecular mechanisms of EnMSC therapy, in the present study, we assessed in parallel the paracrine and therapeutic properties of MSCs derived from endometrium, bone marrow, and adipose tissues in a rat model of myocardial infarction (MI). EnMSCs, BMMSCs, and adipose‐derived MSCs (AdMSCs) were characterized by fluorescence‐activated cell sorting (FACS). Paracrine and cytoprotective actions were assessed in vitro by coculture with neonatal cardiomyocytes and human umbilical vein endothelial cells. A rat MI model was used to compare cell therapy by intramyocardial injection of BMMSCs, AdMSCs, and EnMSCs. We found that EnMSCs conferred superior cardioprotection relative to BMMSCs or AdMSCs and supported enhanced microvessel density. Inhibitor studies indicated that the enhanced paracrine actions of EnMSCs were mediated by secreted exosomes. Analyses of exosomal microRNAs (miRs) by miR array and quantitative polymerase chain reaction revealed that miR‐21 expression was selectively enhanced in exosomes derived from EnMSCs. Selective antagonism of miR‐21 by anti‐miR treatment abolished the antiapoptotic and angiogenic effects of EnMSCs with parallel effects on phosphatase and tensin homolog (PTEN), a miR‐21 target and downstream Akt. The results of the present study confirm the superior cardioprotection by EnMSCs relative to BMMSCs or AdMSCs and implicates miR‐21 as a potential mediator of EnMSC therapy by enhancing cell survival through the PTEN/Akt pathway. The endometrium might be a preferential source of MSCs for cardiovascular cell therapy. Stem Cells Translational Medicine 2017;6:209–222