Extracellular vesicles derived from hypoxia-preconditioned olfactory mucosa mesenchymal stem cells enhance angiogenesis via miR-612.
Extracellular vesicles derived from hypoxia-preconditioned olfactory mucosa mesenchymal stem cells enhance angiogenesis via miR-612.
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源自低氧基于嗅觉粘膜间充质干细胞的细胞外囊泡通过miR-612增强了血管生成。
DOI：
10.1186/s12951-021-01126-6
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发表时间：
2021-11-21
影响因子：
10.2
通讯作者：
Lu M
中科院分区：
文献类型：
--
作者：
Ge L;Xun C;Li W;Jin S;Liu Z;Zhuo Y;Duan D;Hu Z;Chen P;Lu M
间充质干细胞（MSC）在组织修复和再生中发挥重要作用，如诱导血管生成，特别是在缺氧条件下。然而，低氧MSC激活的分子机制仍然很大程度上未知。MSC衍生的细胞外囊泡（EV）是细胞间通讯的重要介质，可直接用作组织修复和再生的治疗剂。本研究旨在探讨人缺氧嗅粘膜间充质干细胞（OM-MSCs）EV对血管生成的影响及其机制。使用差速离心从常氧（N）OM-MSC（N-EV）和缺氧（H）OM-MSC（H-EV）中分离EV，并通过透射电子显微镜和流式细胞术鉴定。在体外和体内，两种类型的OM-MSC-EV促进人脑微血管内皮细胞（HBMEC）的增殖，迁移和血管生成活性。此外，与N-EV组相比，H-EV组的血管生成刺激活性显著增强。MicroRNA分析显示，H-EV中miR-612的丰度高于N-EV，而miR-612失活则消除了N-EV治疗的益处。为了探索miR-612的作用，使用miR-612的模拟物和抑制剂或阿戈米尔和阿克罗米尔进行过表达和敲低实验。使用荧光素酶报告基因测定确认miR-612靶基因。功能获得和功能丧失研究允许验证miR-612（在缺氧OM-MSC-EV中富集）作为功能性信使，其刺激血管生成并通过靶向其3′-非翻译区抑制TP 53的表达。进一步的功能测定显示，低氧OM-MSC-EV通过外泌体miR-612-TP 53-HIF-1α-VEGF轴促进HBMEC中的旁分泌低氧诱导因子1-α（HIF-1α）-血管内皮生长因子（VEGF）信号传导。这些发现表明，低氧OM-MSC-EV可能代表了通过miR-612转移促进血管生成的缺血性疾病的有希望的策略。在线版本包含补充材料，可通过10.1186/s12951-021-01126-6获得。
Mesenchymal stem cells (MSCs) play important roles in tissue repair and regeneration, such as the induction of angiogenesis, particularly under hypoxic conditions. However, the molecular mechanisms underlying hypoxic MSC activation remain largely unknown. MSC-derived extracellular vesicles (EVs) are vital mediators of cell-to-cell communication and can be directly utilized as therapeutic agents for tissue repair and regeneration. Here, we explored the effects of EVs from human hypoxic olfactory mucosa MSCs (OM-MSCs) on angiogenesis and its underlying mechanism. EVs were isolated from normoxic (N) OM-MSCs (N-EVs) and hypoxic (H) OM-MSCs (H-EVs) using differential centrifugation and identified by transmission electron microscopy and flow cytometry. In vitro and in vivo, both types of OM-MSC-EVs promoted the proliferation, migration, and angiogenic activities of human brain microvascular endothelial cells (HBMECs). In addition, angiogenesis-stimulatory activity in the H-EV group was significantly enhanced compared to the N-EV group. MicroRNA profiling revealed a higher abundance of miR-612 in H-EVs than in N-EVs, while miR-612 inactivation abolished the N-EV treatment benefit. To explore the roles of miR-612, overexpression and knock-down experiments were performed using a mimic and inhibitor or agomir and antagomir of miR-612. The miR-612 target genes were confirmed using the luciferase reporter assay. Gain- and loss-of-function studies allowed the validation of miR-612 (enriched in hypoxic OM-MSC-EVs) as a functional messenger that stimulates angiogenesis and represses the expression of TP53 by targeting its 3′-untranslated region. Further functional assays showed that hypoxic OM-MSC-EVs promote paracrine Hypoxia-inducible factor 1-alpha (HIF-1α)-Vascular endothelial growth factor (VEGF) signaling in HBMECs via the exosomal miR-612-TP53-HIF-1α-VEGF axis. These findings suggest that hypoxic OM-MSC-EVs may represent a promising strategy for ischemic disease by promoting angiogenesis via miR-612 transfer. The online version contains supplementary material available at 10.1186/s12951-021-01126-6.
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