Heart to heart: cardiospheres for myocardial regeneration.

Cardiac regenerative therapies seek to grow new myocardium after "irreversible" injury such as myocardial infarction. Various cell types and delivery techniques have been used in experimental models of human disease and clinical trials. When selecting a candidate stem cell type for clinical use, multiple factors need to be taken into consideration. The ability to regenerate myocardium without potentiating arrhythmogenesis is a critical property. Skeletal myoblasts engraft, differentiate, and are arrhythmogenic; in contrast, bone marrow-derived cells do not engraft long-term and have not been associated with excess arrhythmias. Neither cell type, however, achieves true myocardial regeneration. Recognition of the existence of cardiac stem cells and of the ability of mature myocytes to reenter the cell cycle and proliferate has motivated the development of new approaches to cardiac regenerative medicine. Cardiosphere-derived cells decrease scar mass and regenerate viable myocardium both in animal models and in the CADUCEUS (Cardiosphere-Derived Cells For Heart Regeneration After Myocardial Infarction) clinical trial. Although cardiosphere-derived cells fulfill the criteria for stem cells, their stemness appears not to mediate the therapeutic benefit; instead, indirect mechanisms lead to proliferation of the host myocardium. Being of endogenous origin, the newly grown heart muscle is electrically and mechanically well integrated with preexisting myocardial tissue. We hypothesize that cardiac arrhythmias are less likely to complicate cell therapy when the mechanisms of benefit involve secondary proliferation of endogenous myocardium. Conversely, arrhythmias will more likely bedevil therapeutic approaches (such as transplantation of skeletal myoblasts or pluripotent stem cells) that lead to exogenous grafts within the heart, with the degree of coupling and the extent of inhomogeneity being critical determinants of the net effect.