Bone marrow mesenchymal stem cell-derived extracellular vesicles alleviate diabetes-exacerbated atherosclerosis via AMPK/mTOR pathway-mediated autophagy-related macrophage polarization

• DOI: 10.1186/s12933-025-02603-0
• Publication Date: 2025-01-29T21:24:21Z
• Authors: Libo Liu; Ziyu An; Huan Zhang; Xueqi Wan; Xin Zhao; Xueyao Yang; Jinfan Tian; Xiantao Song
• Keywords: Macrophage polarization; Extracellular Vesicles; Exosome

Bone marrow-derived mesenchymal stem cell-derived extracellular vesicles (BMSC-EVs) are widely used for therapeutic purposes in preclinical studies. However, their utility treating diabetes-associated atherosclerosis remains largely unexplored. Here, we aimed to characterize BMSC-EV-mediated regulation of autophagy and macrophage polarization. EVs were isolated from the supernatant cultured BMSCs characterized with transmission electron microscopy (TEM), nanoparticle tracking analysis (NTA), western blotting. A diabetes-related atherosclerotic ApoE−/− mouse model was established through feeding a high-fat diet (HFD) streptozotocin (STZ). Histopathological analyses carried out using Oil Red O, H&E, Masson staining aorta. TEM immunohistochemistry (IHC) applied evaluate autophagy, immunofluorescence (IF) identify RAW264.7 macrophages induced oxidized low-density lipoprotein (ox-LDL) high glucose (HG), co-cultured BMSC-EVs, analyzed proliferation, migration, foam cell formation. cells transduced marker mRFP-GFP-LC3 lentivirus IF Diabetic mice (DA group) had larger aortic plaque areas lower collagen content than HFD mice. BMSC-EV treatment significantly reduced blood glucose, LDL levels, while increasing content. BMSC-EV-treated aortas contained higher number autophagosomes/autolysosomes, increased expression LC3BII correlating decreased P62 levels proportion M1 macrophages. In vitro, BMSC-EVs inhibited formation ox-LDL HG-induced activated cells. These effects reversed by blocker bafilomycin A1. Consistent vivo findings, elevated autophagy-related protein LC3BII/I also expressed markers CD86 iNOS, but showed M2 Arg-1. Further, AMPKα mTOR phosphorylation which blocked AMPK inhibitor compound C. attenuate diabetes-exacerbated inhibiting vascular via AMPK/mTOR signaling-regulated thus hold promise as agents atherosclerosis. Extracellular derived bone marrow may mitigate diabetes-aggravated regulating AMPK/mTOR-mediated polarization formation, cholesterol transport.