Metabolic Conditioning Enhances Human bmMSC Therapy of Doxorubicin-Induced Heart Failure.

The therapeutic potential of bone marrow mesenchymal stromal cells (bmMSCs) to address heart failure needs improvement for better engraftment and survival. This study explores the role of metabolic sorting for human bmMSCs on coculture in vitro and on doxorubicin-induced heart failure mice models. Using functional, epigenetic and gene expression approaches on cells sorted for mitochondrial membrane potential in terms of their metabolic status, we demonstrated that bmMSCs selected for their glycolytic metabolism presented proliferative advantage and resistance to oxidative stress thereby favoring cell engraftment. Therapeutic use of glycolytic bmMSCs rescued left ventricular ejection fraction and decreased fibrosis in mice models of acute heart failure. Metabolic changes were also related to epigenetic histone modifications as lysine methylation. By targeting LSD1 (lysine-specific demethylase 1) as a conditioning agent to enhance the metabolic profile of bmMSCs, we deciphered the interplay between glycolysis and bmMSC functionality. Our study elucidates novel strategies for optimizing bmMSC-based treatments for heart failure, highlighting the metabolic properties of bmMSCs as a promising target for more effective cardiovascular regenerative therapies.

Differences in Mitochondrial Membrane Potential Identify Distinct Populations of Human Cardiac Mesenchymal Progenitor Cells.

Adult human cardiac mesenchymal progenitor cells (hCmPC) are multipotent resident populations involved in cardiac homeostasis and heart repair. Even if the mechanisms have not yet been fully elucidated, the stem cell differentiation is guided by the mitochondrial metabolism; however, mitochondrial approaches to identify hCmPC with enhanced stemness and/or differentiation capability for cellular therapy are not established. Here we demonstrated that hCmPCs sorted for low and high mitochondrial membrane potential (using a lipophilic cationic dye tetramethylrhodamine methyl ester, TMRM), presented differences in energy metabolism from preferential glycolysis to oxidative rates. TMRM-high cells are highly efficient in terms of oxygen consumption rate, basal and maximal respiration, and spare respiratory capacity compared to TMRM-low cells. TMRM-high cells showed characteristics of pre-committed cells and were associated with higher in vitro differentiation capacity through endothelial, cardiac-like, and, to a lesser extent, adipogenic and chondro/osteogenic cell lineage, when compared with TMRM-low cells. Conversely, TMRM-low showed higher self-renewal potential. To conclude, we identified two hCmPC populations with different metabolic profile, stemness maturity, and differentiation potential. Our findings suggest that metabolic sorting can isolate cells with higher regenerative capacity and/or long-term survival. This metabolism-based strategy to select cells may be broadly applicable to therapies.