Metabolic conditioning enhances human bmMSC cell therapy of doxorubicin-induced heart failure

The therapeutic potential of bone marrow mesenchymal stromal cells (bmMSCs) in addressing heart failure need improvement for a better engraftment and survival. This study explores the role of metabolic sorting for human bmMSC on coculture in vitro and on doxorubicin-induced heart failure mice models. Using functional, epigenetic and gene expression approaches on cells sorted on the mitochondrial membrane potential referring their metabolic status, we demonstrated that bmMSC selected for their glycolytic metabolism presented proliferative advantage and resistance to oxidative stress favoring cell engraftment. Therapeutic use of glycolytic bmMSC rescued left ventricular ejection fraction and decrease fibrosis in mice model of acute heart failure. Metabolic changes were also related to epigenetic histone modifications as lysine methylation. Targeting LSD1 (lysine-specific demethylase 1) as a conditioning agent for enhancing the metabolic profile of bmMSC, we decipher the interplay between glycolysis and cell functionality. Our study leads to elucidate novel strategies for optimizing bmMSC-based therapies in treating heart failure and highlight the metabolic properties of bmMSCs as a promising target for more effective cardiovascular regenerative therapies. Overall design: Mesenchymal stromal cells (MSCs) from human bone marrow were sorted based on their Tetramethylrhodamine (TMRM) fluorescence. The low and high populations were isolated into separate tubes, and RNA purification was carried out directly to obtain the highest quality RNAseq data.