远端细胞来源的外泌体通过JAK/STAT-miR-221-E2F2轴促进血管生成,缓解急性呼吸窘迫综合征。

IF 6.3 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
Rongrong Gao, Xu Zhang, Huihui Ju, Yile Zhou, Luoyue Yin, Liuke Yang, Pinwen Wu, Xia Sun, Hao Fang
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引用次数: 0

摘要

急性呼吸窘迫综合征(Acute respiratory distress syndrome, ARDS)以严重的呼吸衰竭和明显的炎症为特征,导致血管和上皮细胞损伤。缺乏有效的药物治疗强调需要新的治疗方法。远端细胞(TCs)是一种新发现的间质细胞类型,在组织修复和血管生成中显示出潜力,特别是通过释放外泌体microRNAs (miRNAs)。外泌体是从LPS(脂多糖)刺激的tc中分离出来的,并使用western blotting和纳米颗粒跟踪分析对其进行了表征。外泌体miR-221在血管生成中的作用通过小鼠血管内皮细胞(MVECs)的管形成、迁移和增殖试验来评估。使用western blotting和qRT-PCR确定JAK/STAT通路参与miR-221调控。双荧光素酶测定证实E2F2是miR-221的直接靶点。通过LPS灌注建立ARDS小鼠模型,通过组织病理学评分、细胞因子分析和内皮屏障完整性分析评估tcs衍生外泌体的治疗效果。我们的研究结果表明,来自lps刺激的TCs的外泌体显著促进mvec的血管生成、增殖和迁移。这些作用是由miR-221介导的,miR-221下调E2F2的表达,E2F2是内皮细胞功能的重要调节因子。JAK/STAT通路在miR-221的产生中起着至关重要的作用,通路抑制可降低miR-221水平并减弱其促血管生成作用。在体内,tcs来源的外泌体减少了ARDS小鼠的肺部炎症和组织损伤,这种作用被miR-221抑制逆转。这些结果表明,tcs来源的外泌体通过JAK/STAT-miR-221-E2F2轴促进血管生成并减轻ARDS。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Telocyte-derived exosomes promote angiogenesis and alleviate acute respiratory distress syndrome via JAK/STAT-miR-221-E2F2 axis.

Acute respiratory distress syndrome (ARDS) is characterized by severe respiratory failure and significant inflammation, leading to vascular and epithelial cell damage. The absence of effective pharmacologic treatments underscores the need for novel therapeutic approaches. Telocytes (TCs), a newly identified type of interstitial cells, have shown potential in tissue repair and angiogenesis, particularly through the release of exosomal microRNAs (miRNAs). Exosomes were isolated from LPS (lipopolysaccharide)-stimulated TCs and characterized using western blotting and nanoparticle tracking analysis. The role of exosomal miR-221 in angiogenesis was assessed through tube formation, migration, and proliferation assays in mouse vascular endothelial cells (MVECs). The JAK/STAT pathway's involvement in miR-221 regulation was determined using western blotting and qRT-PCR. A dual-luciferase assay confirmed E2F2 as a direct target of miR-221. ARDS mouse model was established via LPS instillation, and the therapeutic effects of TCs-derived exosomes were evaluated by histopathological scoring, cytokine analysis, and endothelial barrier integrity assays. Our findings demonstrated that exosomes from LPS-stimulated TCs significantly promoted angiogenesis, proliferation, and migration in MVECs. These effects were mediated by miR-221, which downregulated E2F2 expression, an important regulator of endothelial cell functions. The JAK/STAT pathway played a crucial role in miR-221 production, with pathway inhibition reducing miR-221 levels and attenuating its pro-angiogenic effects. In vivo, TCs-derived exosomes reduced lung inflammation and tissue damage in ARDS mice, effects that were reversed by miR-221 inhibition. These results suggested that TCs-derived exosomes promoted angiogenesis and alleviated ARDS through the JAK/STAT-miR-221-E2F2 axis.

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