Ferroptotic MSCs protect mice against sepsis via promoting macrophage efferocytosis

传出细胞增多 间充质干细胞 巨噬细胞 炎症 败血症 脾脏 吞噬作用 氧化应激 下调和上调 癌症研究 免疫学 化学 医学 病理 内科学 基因 体外 生物化学
作者
Yuchen Pan,Jingman Li,Jiali Wang,Qi Jiang,Jingjing Yang,Huan Dou,Huaping Liang,Kuanyu Li,Yayi Hou
出处
期刊:Cell Death and Disease [Springer Nature]
卷期号:13 (9) 被引量:16
标识
DOI:10.1038/s41419-022-05264-z
摘要

Abstract The therapeutic effect of mesenchymal stem cells (MSCs) on sepsis has been well-known. However, a comprehensive understanding of the relationship between MSCs and macrophages remains elusive. Superparamagnetic iron oxide (SPIO) is one of the most commonly used tracers for MSCs. Our previous study has shown that SPIO enhanced the therapeutic effect of MSCs in a macrophage-dependent manner. However, the fate of SPIO-labeled MSCs (MSC SPIO ) after infusion remains unknown and the direct interaction between MSC SPIO and macrophages remains unclear. Mice were injected intravenously with MSC SPIO at 2 h after Escherichia coli infection and sacrificed at different times to investigate their distribution and therapeutic effect. We found that MSC SPIO homed to lungs rapidly after infusion and then trapped in livers for more than 10 days. Only a few MSC SPIO homed to the spleen and there was no MSC SPIO detectable in the brain, heart, kidney, colon, and uterus. MSC SPIO tended to stay longer in injured organs compared with healthy organs and played a long-term protective role in sepsis. The mRNA expression profiles between MSCs and MSC SPIO were rather different, genes related to lipid metabolism, inflammation, and oxidative stress were changed. The levels of ROS and lipid peroxide were elevated in MSC SPIO , which confirmed that SPIO-induced ferroptosis in MSC SPIO . Ferroptosis of MSC SPIO induced by SPIO enhanced the efferocytosis of macrophages and thus enhanced the protective effect on septic mice, while the benefits were impaired after MSC SPIO were treated with Ferrostatin-1 (Fer-1) or Liproxtatin-1 (Lip-1), the inhibitors of ferroptosis. SPIO-induced ferroptosis in MSCs contributes to better therapeutic effects in sepsis by enhancing the efferocytosis of macrophages. Our data showed the efficacy and advantage of MSC SPIO as a therapeutic tool and the cell states exert different curative effects on sepsis.
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