Excessive branched-chain amino acid accumulation restricts mesenchymal stem cell-based therapy efficacy in myocardial infarction.
Excessive branched-chain amino acid accumulation restricts mesenchymal stem cell-based therapy efficacy in myocardial infarction.
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过多的支链氨基酸积累限制了间充质干细胞治疗心肌梗死的疗效
DOI：
10.1038/s41392-022-00971-7
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发表时间：
2022-06-03
影响因子：
39.3
通讯作者：
Tao, Ling
中科院分区：
文献类型：
--
作者：
Zhang, Fuyang;Hu, Guangyu;Chen, Xiyao;Zhang, Ling;Guo, Lanyan;Li, Congye;Zhao, Hang;Cui, Zhe;Guo, Xiong;Sun, Fangfang;Song, Dandan;Yan, Wenjun;Xia, Yunlong;Wang, Shan;Fan, Miaomiao;Tao, Ling
间充质干细胞（Mesenchymal stem cells，MSC）移植到缺血后心脏环境中的存活率和留存率较低，限制了MSC治疗的心脏修复效果。慢性缺血导致心脏中的代谢重编程，但对这些代谢变化如何影响植入的MSC知之甚少。在这里，我们发现过度的支链氨基酸（BCAA）积累，在缺血后心脏中看到的代谢特征，不利于心肌内注射的MSC的保留和心脏保护。发现驱动的实验表明，病理水平的BCAA通过加速组蛋白3赖氨酸9三甲基化（H3 K9 me 3）的丧失使MSC对应激诱导的细胞死亡和过早衰老敏感。新的mTORC 1/DUX 4/KDM 4 E轴被鉴定为BCAA诱导的H3 K9 me 3丢失和不良表型获得的原因。通过遗传/药理学方法增强MSC中的BCAA分解代谢能力，极大地改善了它们对高BCAA环境的适应，并增强了它们的心脏保护功效。我们的结论是，异常BCAA积累是有害的植入间充质干细胞通过一个以前未知的代谢信号表观遗传机制，强调缺血后心脏的代谢变化至关重要的影响植入间充质干细胞的命运和他们的治疗效益。
Mesenchymal stem cells (MSCs) delivered into the post-ischemic heart milieu have a low survival and retention rate, thus restricting the cardioreparative efficacy of MSC-based therapy. Chronic ischemia results in metabolic reprogramming in the heart, but little is known about how these metabolic changes influence implanted MSCs. Here, we found that excessive branched-chain amino acid (BCAA) accumulation, a metabolic signature seen in the post-ischemic heart, was disadvantageous to the retention and cardioprotection of intramyocardially injected MSCs. Discovery-driven experiments revealed that BCAA at pathological levels sensitized MSCs to stress-induced cell death and premature senescence via accelerating the loss of histone 3 lysine 9 trimethylation (H3K9me3). A novel mTORC1/DUX4/KDM4E axis was identified as the cause of BCAA-induced H3K9me3 loss and adverse phenotype acquisition. Enhancing BCAA catabolic capability in MSCs via genetic/pharmacological approaches greatly improved their adaptation to the high BCAA milieu and strengthened their cardioprotective efficacy. We conclude that aberrant BCAA accumulation is detrimental to implanted MSCs via a previously unknown metabolite-signaling-epigenetic mechanism, emphasizing that the metabolic changes of the post-ischemic heart crucially influence the fate of implanted MSCs and their therapeutic benefits.
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影响因子：
29
作者：
Li T;Zhang Z;Kolwicz SC Jr;Abell L;Roe ND;Kim M;Zhou B;Cao Y;Ritterhoff J;Gu H;Raftery D;Sun H;Tian R
通讯作者：
Tian R
影响因子：
15.9
作者：
Lu, Gang;Sun, Haipeng;Wang, Yibin
通讯作者：
Wang, Yibin
影响因子：
16.6
作者：
Shao D;Villet O;Zhang Z;Choi SW;Yan J;Ritterhoff J;Gu H;Djukovic D;Christodoulou D;Kolwicz SC Jr;Raftery D;Tian R
通讯作者：
Tian R
影响因子：
8.2
作者：
Mahendran, Yuvaraj;Jonsson, Anna;Hansen, Torben
通讯作者：
Hansen, Torben
影响因子：
16.6
作者：
Kaya-Okur, Hatice S.;Wu, Steven J.;Henikoff, Steven
通讯作者：
Henikoff, Steven