Mitochondrial Membrane Potential Identifies Cells with Enhanced Stemness for Cellular Therapy.
Mitochondrial Membrane Potential Identifies Cells with Enhanced Stemness for Cellular Therapy.
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DOI：
10.1016/j.cmet.2015.11.002
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发表时间：
2016-01-12
期刊：
影响因子：
29
通讯作者：
Restifo NP
中科院分区：
文献类型：
--
作者：
Sukumar M;Liu J;Mehta GU;Patel SJ;Roychoudhuri R;Crompton JG;Klebanoff CA;Ji Y;Li P;Yu Z;Whitehill GD;Clever D;Eil RL;Palmer DC;Mitra S;Rao M;Keyvanfar K;Schrump DS;Wang E;Marincola FM;Gattinoni L;Leonard WJ;Muranski P;Finkel T;Restifo NP
过继转移的CD8+ T细胞的长期存活和抗肿瘤免疫力取决于它们的代谢适应性，但是基于代谢特征分离治疗性T细胞的方法还没有很好地建立。在这里，我们利用亲脂性阳离子染料四甲基罗丹明甲酯（TMRM），以确定和分离代谢稳健的T细胞的基础上，他们的线粒体膜电位（Δ μ m）。综合代谢组学和基因表达谱分析表明，低Δ Km分选的CD8+ T细胞的代谢适应性改善具有全局特征。与高Δ Δ m细胞相比，这些低Δ Δ m T细胞的转移与上级体内持久性和增强的根除已建立肿瘤的能力相关。在CD8+、CD4+ T细胞亚群和长期造血干细胞中观察到使用基于Δ Tm的分选富集具有上级代谢特征的细胞。这种基于代谢的细胞选择方法可能广泛适用于涉及HSC或淋巴细胞转移的治疗，用于治疗病毒相关疾病和癌症。
Long-term survival and anti-tumor immunity of adoptively-transferred CD8+ T cells is dependent on their metabolic fitness, but approaches to isolate therapeutic T cells based on metabolic features are not well established. Here we utilized a lipophilic cationic dye tetramethylrhodamine methyl ester (TMRM) to identify and isolate metabolically-robust T cells based on their mitochondrial membrane potential (ΔΨm). Comprehensive metabolomic and gene expression profiling demonstrated global features of improved metabolic fitness in low-ΔΨm-sorted CD8+ T cells. Transfer of these low-ΔΨm T cells was associated with superior long-term in vivo persistence and an enhanced capacity to eradicate established tumors compared with high-ΔΨm cells. Use of ΔΨm-based sorting to enrich for cells with superior metabolic features was observed in CD8+, CD4+ T-cell subsets and long-term hematopoietic stem cells. This metabolism-based approach to cell-selection may be broadly applicable to therapies involving the transfer of HSC or lymphocytes for the treatment of viral-associated illnesses and cancer.