GSE183027
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 [CUT&Tag]
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. Overall design: CUT&Tag (H3K9me3) of ADSCs treated with vehicle or BCAA