【罂粟摘要】肌成纤维细胞来源的外泌体引起心脏内皮细胞功能障碍
肌成纤维细胞来源的外泌体引起心脏内皮细胞功能障碍
贵州医科大学 高鸿教授课题组
翻译：周菁 编辑：佟睿 审校：曹莹
内皮细胞（ECS）在维持血管稳态和心脏功能方面发挥着关键作用。结果表明，活化的成纤维细胞衍生的外泌体损害肥厚性心脏心肌细胞功能，但它们对ECS的影响尚不清楚。因此，我们假设激活的心肌成纤维细胞衍生的外泌体（FB-EXO）介导EC功能障碍，因此调节心肌成纤维细胞外泌体含量可以改善内皮功能。
从心肌成纤维细胞（FB） - 调节剂中分离出外泌体，并通过纳米颗粒跟踪分析和电子显微镜表征。从小鼠心脏中分离出内皮细胞。用从FB为条件的培养液中分离的外泌体处理内皮细胞，再用转化生长因子-β1(TGF-β1-FB-Exo)或磷酸盐(对照组)处理FB。血管内皮细胞功能受损(表现为血管内皮生长因子-A、HIF-1α、CD31和血管生成素1基因表达降低，管状形成和细胞迁移减少)。β-FB-Exo处理的细胞表现为血管内皮细胞功能减退(表现为血管内皮生长因子-A、HIF1mRNA、CD31mRNA和血管生成素1基因表达降低)。此外，转化生长因子-β1-FB-Exo处理的内皮细胞与对照组相比，细胞增殖减少，凋亡增加。转化生长因子受体-β1-FB-Exo Cargo分析显示纤维化相关miRNA发生改变，包括miR-200A-3p水平显著升高。有趣的是，miR-200A-3p抑制活化的FBS，减轻转化生长因子-β1-FB-Exo介导的内皮功能障碍。
综上所述，本研究证实了激活的成纤维细胞来源的外泌体中富集的miR-200a-3p对内皮细胞生物学和功能的重要作用。
Ranjan P, Kumari R, Goswami SK, et al，Myofibroblast-Derived Exosome Induce Cardiac Endothelial Cell Dysfunction.Front Cardiovasc Med 2021;8
Myofibroblast-Derived Exosome Induce Cardiac Endothelial Cell Dysfunction.
Background: Endothelial cells (ECs) play a critical role in the maintenance of vascular homeostasis and in heart function. It was shown that activated fibroblast-derived
exosomes impair cardiomyocyte function in hypertrophic heart, but their effect on ECs is not yet clear. Thus, we hypothesized that activated cardiac fibroblast-derived exosomes(FB-Exo) mediate EC dysfunction, and therefore modulation of FB-exosomal contents may improve endothelial function.
Methods and Results: Exosomes were isolated from cardiac fibroblast (FB)-conditioned media and characterized by nanoparticle tracking analysis and electron microscopy. ECs were isolated from mouse heart. ECs were treated with exosomes isolated from FB-conditioned media, following FB culture with TGF-β1 (TGF-β1-FB-Exo) or PBS (control) treatment. TGF-β1 significantly activated fibroblasts as shown by increase in collagen type1 α1 (COL1α1), periostin (POSTN), and fibronectin (FN1) gene expression and increase in Smad2/3 and p38 phosphorylation. Impaired endothelial cell function (as characterized by a decrease in tube formation and cell migration along with reduced VEGF-A, Hif1α, CD31, and angiopoietin1 gene expression) was observed in TGF-β1-FB-Exo treated cells. Furthermore, TGF-β1-FB-Exo treated ECs showed reduced cell proliferation and increased apoptosis as compared to control cells. TGF-β1-FB-Exo cargo analysis revealed an alteration in fibrosis-associated miRNAs, including a significant increase in miR-200a-3p level. Interestingly, miR-200a-3p inhibition in activated FBs, alleviated TGF-β1-FB-Exo-mediated endothelial dysfunction.
Conclusions: Taken together, this study demonstrates an important role of miR-200a-3p enriched within activated fibroblast-derived exosomes on endothelial cell biology and function.