Background-Human induced pluripotent stem cell-derived cardiomyocytes (hiPS-CMs) are a promising source of cells for regenerating myocardium. However, several issues, especially the large-scale preparation of hiPS-CMs and elimination of undifferentiated iPS cells, must be resolved before hiPS cells can be used clinically. The cell-sheet technique is one of the useful methods for transplanting large numbers of cells. We hypothesized that hiPS-CM-sheet transplantation would be feasible, safe, and therapeutically effective for the treatment of ischemic cardiomyopathy. Methods and Results-Human iPS cells were established by infecting human dermal fibroblasts with a retrovirus carryingOct3/4, Sox2, Klf4, and c-Myc. Cardiomyogenic differentiation was induced by WNT signaling molecules, yielding hiPS-CMs that were almost 90% positive for ␣-actinin, Nkx2.5, and cardiac troponin T. hiPS-CM sheets were created using thermoresponsive dishes and transplanted over the myocardial infarcts in a porcine model of ischemic cardiomyopathy induced by ameroid constriction of the left anterior descending coronary artery (nϭ6 for the iPS group receiving sheet transplantation and the sham-operated group; both groups received tacrolimus daily). Transplantation significantly improved cardiac performance and attenuated left ventricular remodeling. hiPS-CMs were detectable 8 weeks after transplantation, but very few survived long term. No teratoma formation was observed in animals that received hiPS-CM sheets. Conclusions-The culture system used yields a large number of highly pure hiPS-CMs, and hiPS-CM sheets could improve cardiac function after ischemic cardiomyopathy. This newly developed culture system and the hiPS-CM sheets may provide a basis for the clinical use of hiPS cells in cardiac regeneration therapy. Key Words: pluripotent stem cell Ⅲ regeneration therapy Ⅲ transplantation T he myocardium has limited regenerative capacity, and loss of myocardium due to myocardial infarction therefore leads to heart failure. Despite remarkable recent progress in medical and surgical treatments for heart failure, end-stage heart failure remains a leading cause of morbidity and mortality. 1 Therefore, the myocardium is one of the most important targets in regenerative medicine. Cell therapy has been introduced as a new treatment for heart failure. Clinical trials using bone marrow cells and myoblasts are underway; although these cells improve cardiac performance, chiefly through paracrine cytokine effects, they show limited differentiation into cardiomyocytes. 2 Induced pluripotent stem (iPS) cells were first generated by nuclear reprogramming of mouse fibroblasts in 2006, 3 and human iPS (hiPS) cells were established in 2007 by the transduction of defined factors. 4,5 The production of hiPS cells poses fewer legal and ethical issues than does the generation of human embryonic stem (ES) cells. In addition, recent studies have demonstrated methods for the highly efficient production from hiPS cells of cardiomyocytes with typical electrophysio...

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Dilated cardiomyopathy (DCM) is a heart muscle disease characterized by progressive heart failure, and is a leading cause of mortality and morbidity. Recently, cellular therapy for end-stage heart failure has been emerging. We herein report a 56-year-old male who received a transplant of autologous myoblast sheets manufactured in temperature-responsive culture dishes. His clinical condition improved markedly, leaving him without any arrhythmia and able to discontinue using a left ventricular assist system and avoid cardiac transplantation. These findings suggest that cellular therapy using myoblast sheets is a promising new strategy for treating patients with end-stage DCM. This method might be an effective alternative to heart transplantation in the near future.