Department of Cardiology, Xijing Hospital, the Fourth Military Medical University, 710032, Xi'an, China.
Department of Geriatrics, Xijing Hospital, the Fourth Military Medical University, 710032, Xi'an, China.
Signal Transduct Target Ther. 2022 Jun 3;7(1):171. doi: 10.1038/s41392-022-00971-7.
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.
间充质干细胞（MSCs）移植到缺血后的心脏环境中，存活率和保留率较低，从而限制了基于 MSC 的治疗的心脏修复效果。慢性缺血会导致心脏代谢重编程，但人们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，即缺血后心脏中出现的一种代谢特征，不利于心肌内注射的 MSC 的保留和心脏保护。基于发现的实验表明，病理水平的 BCAA 通过加速组蛋白 3 赖氨酸 9 三甲基化（H3K9me3）的丧失，使 MSC 对应激诱导的细胞死亡和过早衰老敏感。确定了一条新的 mTORC1/ DUX4/ KDM4E 轴作为 BCAA 诱导的 H3K9me3 丢失和不良表型获得的原因。通过遗传/药物方法增强 MSC 中的 BCAA 代谢能力，极大地改善了它们对高 BCAA 环境的适应能力，并增强了它们的心脏保护作用。我们得出结论，异常的 BCAA 积累通过一种以前未知的代谢物信号转导表观遗传机制对植入的 MSC 有害，强调了缺血后心脏的代谢变化对植入的 MSC 的命运及其治疗效果有至关重要的影响。
