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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]

ABSTRACT: 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.

ORGANISM(S): Rattus norvegicus

PROVIDER: GSE183025 | GEO | 2021/09/02

REPOSITORIES: GEO

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