血小板衍生细胞外囊泡对病毒性心肌炎的治疗作用与生物分子含量相关。
Therapeutic effects of platelet-derived extracellular vesicles on viral myocarditis correlate with biomolecular content.
作者信息
Beetler Danielle J, Giresi Presley, Di Florio Damian N, Fliess Jessica J, McCabe Elizabeth J, Watkins Molly M, Xu Vivian, Auda Matthew E, Bruno Katelyn A, Whelan Emily R, Kocsis Stephen P C, Edenfield Brandy H, Walker Sierra A, Macomb Logan P, Keegan Kevin C, Jain Angita, Morales-Lara Andrea C, Chekuri Isha, Hill Anneliese R, Farres Houssam, Wolfram Joy, Behfar Atta, Stalboerger Paul G, Terzic Andre, Cooper Leslie T, Fairweather DeLisa
机构信息
Department of Cardiovascular Medicine, Mayo Clinic, Jacksonville, FL, United States.
Center for Clinical and Translational Science, Mayo Clinic, Rochester, MN, United States.
出版信息
Front Immunol. 2025 Jan 6;15:1468969. doi: 10.3389/fimmu.2024.1468969. eCollection 2024.
INTRODUCTION
Extracellular vesicles (EVs) can potently inhibit inflammation yet there is a lack of understanding about the impact of donor characteristics on the efficacy of EVs. The goal of this study was to determine whether the sex and age of donor platelet-derived EVs (PEV) affected their ability to inhibit viral myocarditis.
METHODS
PEV, isolated from men and women of all ages, was compared to PEV obtained from women under 50 years of age, which we termed premenopausal PEV (pmPEV). Because of the protective effect of estrogen against myocardial inflammation, we hypothesized that pmPEV would be more effective than PEV at inhibiting myocarditis. We injected PEV, pmPEV, or vehicle control in a mouse model of viral myocarditis and examined histology, gene expression, protein profiles, and performed proteome and microRNA (miR) sequencing of EVs.
RESULTS
We found that both PEV and pmPEV significantly inhibited myocarditis; however, PEV was more effective, which was confirmed by a greater reduction of inflammatory cells and proinflammatory and profibrotic markers determined using gene expression and immunohistochemistry. Proteome and miR sequencing of EVs revealed that PEV miRs specifically targeted antiviral, Toll-like receptor (TLR)4, and inflammasome pathways known to contribute to myocarditis while pmPEV contained general immunoregulatory miRs.
DISCUSSION
These differences in EV content corresponded to the differing anti-inflammatory effects of the two types of EVs on viral myocarditis.
引言
细胞外囊泡（EVs）能够有效抑制炎症，但目前对于供体特征对EVs疗效的影响尚缺乏了解。本研究的目的是确定供体血小板衍生的细胞外囊泡（PEV）的性别和年龄是否会影响其抑制病毒性心肌炎的能力。
方法
将从各年龄段男性和女性中分离得到的PEV与从50岁以下女性中获得的PEV进行比较，我们将后者称为绝经前PEV（pmPEV）。由于雌激素对心肌炎症具有保护作用，我们推测pmPEV在抑制心肌炎方面比PEV更有效。我们在病毒性心肌炎小鼠模型中注射PEV、pmPEV或载体对照，并检查组织学、基因表达、蛋白质谱，同时对细胞外囊泡进行蛋白质组和微小RNA（miR）测序。
结果
我们发现PEV和pmPEV均能显著抑制心肌炎；然而，PEV的效果更佳，这通过基因表达和免疫组织化学检测显示炎症细胞以及促炎和促纤维化标志物的减少更为明显得到证实。对细胞外囊泡的蛋白质组和miR测序表明，PEV中的miRs特异性靶向已知与心肌炎相关的抗病毒、Toll样受体（TLR）4和炎性小体途径，而pmPEV则包含一般免疫调节性miRs。
讨论
细胞外囊泡内容物的这些差异与两种类型的细胞外囊泡对病毒性心肌炎的不同抗炎作用相对应。
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