Department of Cardiology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China.
Cardiovascular Disease Center, The Central Hospital of Enshi Tujia and Miao Autonomous Prefecture, Enshi Clinical College of Wuhan University, No. 158 Wuyang Avenue, Enshi, Hubei, China.
Stem Cell Res Ther. 2024 Aug 4;15(1):242. doi: 10.1186/s13287-024-03808-y.
Mesenchymal stromal cell (MSC)-derived exosomes (MSC-Exo) have been recognized for their significant role in regulating macrophage polarization, a process crucial to the pathogenesis of abdominal aortic aneurysm (AAA). However, the therapeutic effects of MSC-Exo on AAA remain largely unexplored. Therefore, this study aimed to investigate the functional and mechanistic aspects of MSC-Exo in the progression of AAA.
The MSC-derived exosomes were characterized using Transmission Electron Microscopy, Nanoparticle Tracking Analysis, and Western blotting. An experimental mouse model of AAA was established through the administration of angiotensin II (Ang II) in male apoe mice and calcium chloride (CaCl) in male C57/B6 mice, with subsequent tail vein injection of exosomes to evaluate their efficacy against AAA. Macrophage polarization was assessed using immunofluorescence staining and WB analysis. Mechanistic analysis was performed using 4D Label-free Proteomics analysis.
We found that intravenous administration of MSC-Exo induced M2 polarization of macrophages within an inflammatory environment, effectively impeding AAA development in Ang II or CaCl-induced AAA model. The therapeutic efficacy of MSC-Exo treatment was dependent on the presence of macrophages. Mechanistically, MSC-Exo suppressed the levels of cluster of differentiation 74 (CD74), modulating macrophage polarization through the TSC2-mTOR-AKT pathway. These findings highlight the potential of MSC-Exo as a therapeutic strategy for AAA by modulating macrophage polarization.
间充质干细胞（MSC）衍生的外泌体（MSC-Exo）在调节巨噬细胞极化方面的作用已得到广泛认可，而巨噬细胞极化是腹主动脉瘤（AAA）发病机制的关键过程。然而，MSC-Exo 治疗 AAA 的疗效在很大程度上仍未得到探索。因此，本研究旨在探讨 MSC-Exo 在 AAA 进展中的功能和机制方面。
使用透射电子显微镜、纳米颗粒跟踪分析和 Western blot 对 MSC 衍生的外泌体进行了表征。通过向雄性 apoE 小鼠给予血管紧张素 II（Ang II）和雄性 C57/B6 小鼠给予氯化钙（CaCl）建立 AAA 实验小鼠模型，并通过尾静脉注射外泌体评估其对 AAA 的疗效。使用免疫荧光染色和 WB 分析评估巨噬细胞极化。使用 4D 无标记蛋白质组学分析进行机制分析。
我们发现，静脉内给予 MSC-Exo 可在炎症环境中诱导巨噬细胞 M2 极化，有效阻止 Ang II 或 CaCl 诱导的 AAA 模型中 AAA 的发展。MSC-Exo 治疗的疗效依赖于巨噬细胞的存在。从机制上讲，MSC-Exo 抑制了分化簇 74（CD74）的水平，通过 TSC2-mTOR-AKT 通路调节巨噬细胞极化。这些发现强调了 MSC-Exo 通过调节巨噬细胞极化作为 AAA 治疗策略的潜力。
