Mesenchymal Stem Cell-Derived Extracellular Vesicles Alleviate Acute Lung Injury Via Transfer of miR-27a-3p*
Mesenchymal Stem Cell-Derived Extracellular Vesicles Alleviate Acute Lung Injury Via Transfer of miR-27a-3p*
复制标题
间充质干细胞衍生的细胞外囊泡通过 miR-27a-3p 的转移减轻急性肺损伤
DOI：
10.1097/ccm.0000000000004315
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发表时间：
2020-07-01
影响因子：
8.8
通讯作者：
Xu, Jianguo
中科院分区：
文献类型：
--
作者：
Wang, Jiangmei;Huang, Ruoqiong;Xu, Jianguo
目的：本研究的目的是确定microRNA转移在介导间充质干细胞衍生的细胞外囊泡在急性肺损伤中的作用。设计：实验细胞和动物研究。设置：大学的研究实验室。受试者：THP-1单核细胞、骨髓源性巨噬细胞和C57 BL/6小鼠。干预措施：为了确定体外microRNA转移，将间充质干细胞和间充质干细胞衍生的细胞外囊泡与THP-1细胞和骨髓衍生的巨噬细胞一起培养，然后测定靶细胞中的microRNA表达。为了研究microRNA转移在体内的作用，将间充质干细胞衍生的细胞外囊泡给予脂多糖诱导的肺损伤小鼠。测量和主要结果：间充质干细胞衍生的细胞外囊泡在体外和体内均被巨噬细胞有效吸收。miR-27 a-3 p是微阵列分析中THP-1细胞中最高表达的microRNA之一，并且从间充质干细胞和间充质干细胞衍生的细胞外囊泡转移到THP-1/骨髓衍生的巨噬细胞。间充质干细胞衍生的细胞外囊泡促进骨髓衍生的巨噬细胞中的M2极化，这被慢病毒抗miR-27 a-3 p转导抑制。间充质干细胞衍生的细胞外囊泡全身和脑内给药与间充质干细胞在缓解急性肺损伤、升高肺泡巨噬细胞中的miR-27 a-3 p水平和促进M2巨噬细胞极化方面一样有效。间充质干细胞衍生的细胞外囊泡的治疗同时降低了肺泡巨噬细胞核因子κ B亚基1的表达，这是miR-27 a-3 p的靶点。用抗miR-27 a-3 p慢病毒转导间充质干细胞或在体内敲低miR-27 a-3 p消除了间充质干细胞衍生的细胞外囊泡对急性肺损伤和M2巨噬细胞极化的影响。结论：间充质干细胞衍生的细胞外囊泡至少部分地通过将miR-27 a-3 p转移至肺泡巨噬细胞来减轻急性肺损伤。miR-27 a-3 p作用于靶向NFKB 1，并且是M2巨噬细胞极化的关键调节剂。
Objectives: The goal of this study was to determine the role of microRNA transfer in mediating the effects of mesenchymal stem cell-derived extracellular vesicles in acute lung injury. Design: Experimental cell and animal studies. Setting: University-based research laboratory. Subjects: THP-1 monocytes, bone marrow-derived macrophages, and C57BL/6 mice. Interventions: To determine the microRNA transfer in vitro, mesenchymal stem cells and mesenchymal stem cell-derived extracellular vesicles were cultured with THP-1 cells and bone marrow-derived macrophages and then assayed for microRNA expression in the target cells. To examine the role of microRNA transfer in vivo, mesenchymal stem cell-derived extracellular vesicles were administered to mice with lipopolysaccharide-induced lung injury. Measurements and Main Results: Mesenchymal stem cell-derived extracellular vesicles were efficiently taken up by macrophages in vitro and in vivo. miR-27a-3p was one of the most highly expressed microRNAs in THP-1 cells in microarray analysis and was transferred from mesenchymal stem cells and mesenchymal stem cell-derived extracellular vesicles to THP-1/bone marrow-derived macrophages. Mesenchymal stem cell-derived extracellular vesicles promoted M2 polarization in bone marrow-derived macrophages, which was inhibited by lentiviral anti-miR-27a-3p transduction. Mesenchymal stem cell-derived extracellular vesicles administered systemically and intratracheally were as effective as mesenchymal stem cells in alleviating acute lung injury, elevating miR-27a-3p levels in alveolar macrophages, and promoting M2 macrophage polarization. Treatment of mesenchymal stem cell-derived extracellular vesicles concurrently decreased alveolar macrophage expression of nuclear factor kappa B subunit 1, a target of miR-27a-3p. Lentiviral transduction of mesenchymal stem cells with anti-miR-27a-3p or knockdown of miR-27a-3p in vivo abolished the effects of mesenchymal stem cell-derived extracellular vesicles on acute lung injury and M2 macrophage polarization. Conclusions: Mesenchymal stem cell-derived extracellular vesicles mitigate acute lung injury at least partially via transferring miR-27a-3p to alveolar macrophages. miR-27a-3p acts to target NFKB1 and is a crucial regulator of M2 macrophage polarization.