Excessive Branched Chain Amino Acid Accumulation Creates an Unfavourable Myocardial Milieu that Inhibits the Cardioprotective Effects of Implanted Mesenchymal Stem Cells in Ischemic Heart Injury [RNA-Seq]

Myocardial infarction (MI) causes cardiac metabolic reprogramming and results in robust changes in intramyocardial metabolite composition, but little is known about how these metabolic changes influence the fate of implanted stem cells. We found that excessive branched chain amino acid (BCAA) accumulation, a metabolic signature of the post-infarcted heart, created an unfavorable milieu inhibiting the retention and cardioprotection of intramyocardially-delivered mesenchymal stem cells (MSCs). BCAA at pathological levels sensitized MSCs to the acquisition of a injured phenotype by suppressing the histone H3K9 trimethylation (H3K9me3) modification. Furthermore, a novel mTORC1/DUX4/KDM4E axis was identified as the cause of the H3K9me3 loss and adverse phenotype acquisition induced by BCAA. Enhancing BCAA catabolism in MSCs via genetic or pharmacological approaches improved their adaptation to the extracellular BCAA milieu and strengthened their cardioprotective efficacy. These findings reveal a critical role of myocardial metabolic reprogramming in regulating the fate and cardioprotection of implanted MSCs after MI.心肌梗死（Myocardial infarction, MI）可引发心脏代谢重编程，导致心肌内代谢物组成发生显著变化，但目前对于此类代谢改变如何影响植入干细胞的命运仍知之甚少。本研究发现，梗死后心脏的代谢特征为支链氨基酸（branched chain amino acid, BCAA）过度蓄积，该过程会构建不利微环境，抑制心肌内递送的间充质干细胞（mesenchymal stem cells, MSCs）的滞留能力与心脏保护作用。病理水平的支链氨基酸可通过抑制组蛋白H3K9三甲基化（histone H3K9 trimethylation, H3K9me3）修饰，使间充质干细胞更易获得损伤表型。此外，本研究还鉴定出一条全新的mTORC1/DUX4/KDM4E信号轴，其介导了支链氨基酸诱导的H3K9me3丢失及间充质干细胞不良表型的获得。通过基因或药理学手段增强间充质干细胞的支链氨基酸分解代谢能力，可改善其对细胞外支链氨基酸微环境的适应性，并强化其心脏保护效能。上述研究结果揭示了心肌代谢重编程在调控心肌梗死后植入间充质干细胞的命运及其心脏保护作用中的关键作用。