The ATP synthase inhibition induces an AMPK-dependent glycolytic switch of mesenchymal stem cells that enhances their immunotherapeutic potential.
The ATP synthase inhibition induces an AMPK-dependent glycolytic switch of mesenchymal stem cells that enhances their immunotherapeutic potential.
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ATP合酶抑制作用诱导间充质干细胞的AMPK依赖性糖酵解开关，从而增强其免疫治疗势。
DOI：
10.7150/thno.51631
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发表时间：
2021
期刊：
影响因子：
12.4
通讯作者：
Luz-Crawford P
中科院分区：
文献类型：
--
作者：
Contreras-Lopez R;Elizondo-Vega R;Luque-Campos N;Torres MJ;Pradenas C;Tejedor G;Paredes-Martínez MJ;Vega-Letter AM;Campos-Mora M;Rigual-Gonzalez Y;Oyarce K;Salgado M;Jorgensen C;Khoury M;Garcia-Robles MLÁ;Altamirano C;Djouad F;Luz-Crawford P
目的：间充质干细胞/基质细胞（MSC）因其强大的免疫调节能力而成为炎症性疾病的治疗工具。它们的抑制活性主要依赖于炎症线索，这些炎症线索最近与MSC生物能量状态向糖酵解代谢的变化有关。然而，这种代谢重编程背后的分子机制及其对间充质干细胞治疗特性的影响尚未得到研究。方法：使用促炎细胞因子、ATP合成酶抑制剂（寡霉素）或2-脱氧-d -葡萄糖（2DG）对人和小鼠来源的间充质干细胞进行代谢重编程。这些细胞的免疫抑制活性在体外用促炎T细胞共培养实验和体内用延迟型超敏反应（DTH）和图抗宿主病（GVHD）小鼠模型进行了测试。结果：我们发现寡霉素介导的MSC前糖酵解开关在体外显著增强其免疫抑制特性。相反，使用2DG抑制糖酵解可显著降低MSC的免疫调节作用。此外，在体内，MSC糖酵解重编程显著增加了它们在DTH和GVHD小鼠模型中的治疗效果。最后，我们证明了MSC糖酵解开关效应部分取决于AMPK信号通路的激活。结论：总之，我们的研究结果表明，使用ATP合酶抑制剂对MSC进行ampk依赖性糖酵解重编程有助于其免疫抑制和治疗功能，并提示前糖酵解药物可能用于改善MSC为基础的治疗。
Objectives: Mesenchymal Stem/Stromal Cells (MSC) are promising therapeutic tools for inflammatory diseases due to their potent immunoregulatory capacities. Their suppressive activity mainly depends on inflammatory cues that have been recently associated with changes in MSC bioenergetic status towards a glycolytic metabolism. However, the molecular mechanisms behind this metabolic reprogramming and its impact on MSC therapeutic properties have not been investigated. Methods: Human and murine-derived MSC were metabolically reprogramed using pro-inflammatory cytokines, an inhibitor of ATP synthase (oligomycin), or 2-deoxy-D-glucose (2DG). The immunosuppressive activity of these cells was tested in vitro using co-culture experiments with pro-inflammatory T cells and in vivo with the Delayed-Type Hypersensitivity (DTH) and the Graph versus Host Disease (GVHD) murine models. Results: We found that the oligomycin-mediated pro-glycolytic switch of MSC significantly enhanced their immunosuppressive properties in vitro. Conversely, glycolysis inhibition using 2DG significantly reduced MSC immunoregulatory effects. Moreover, in vivo, MSC glycolytic reprogramming significantly increased their therapeutic benefit in the DTH and GVHD mouse models. Finally, we demonstrated that the MSC glycolytic switch effect partly depends on the activation of the AMPK signaling pathway. Conclusion: Altogether, our findings show that AMPK-dependent glycolytic reprogramming of MSC using an ATP synthase inhibitor contributes to their immunosuppressive and therapeutic functions, and suggest that pro-glycolytic drugs might be used to improve MSC-based therapy.