Cardiac repair and regeneration: cell therapy, in vivo reprogramming, and the promise of extracellular vesicles.

Therapeutic interventions to replenish lost cardiomyocytes and recover myocardium functions following ischemic myocardial infarction (MI) remain major goals in the cardiac regeneration field. Clinical trials harnessing autologous or allogeneic cell therapy approaches from both cardiac and noncardiac cells sources, thus far, demonstrate marginal improvement. Moreover, complications such as arrythmias and graft rejections associated with cellular or organ-based therapies continue to prevail. Extracellular vesicles, on the other hand, are cell-derived, nano-sized, cargo-containing biomolecules that have emerged as potent alternatives to cell-based cardiac regeneration/replacement therapy. Recent studies demonstrate that most stem-cell-derived extracellular vesicles (Stem-EVs) are nonimmunogenic and carry cardioprotective therapeutic cargos. Moreover, administration of multiple Stem-EV types in animal models of acute MI results in reduced inflammation, apoptosis, smaller infarct size and improved cardiac functionality. With recent developments, engineered Stem-EVs with enhanced cardiac targeting, prolonged circulation and recombinant therapeutic cargos may tilt the cardiac regeneration field toward these novel cell-free biologics. Here we provide a brief overview of current approaches to repair and replenish damaged cardiomyocytes following MI via cell therapy and in vivo reprogramming, and we delve deeply into the therapeutic potentials of Stem-EVs in cardiac repair and regeneration.