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...
The respective volumes of hepatic tumors and nontumorous parenchyma of 50 patients requiring hepatectomy of more than one segment of Healey for tumor removal were measured using computed tomography (Vol-CT). The volume estimated by Vol-CT was found to correlate with the real weight resected (P < .0001) with a mean absolute error of 64.9 mL. The ratio of the nontumorous parenchymal volume of the resected liver to that of the whole liver (R2) in 15 patients who underwent right or extended right hepatic lobectomy was 43% +/- 15%. Eight of 15 patients with R2s < 60% underwent the procedures without right portal vein embolization (PE). The other seven with R2s exceeding 60% or an indocyanine green retention rate after 15 minutes (ICG15) of 10% to 20% underwent PE: in six of seven, the nontumorous parenchyma of the right hepatic lobe became atrophic and in all seven, the volume of the remaining left hepatic lobe increased with a decrease in the mean R2 from 62% +/- 14% to 55% +/- 8% (P = .0006). In the remaining 35 who underwent other hepatectomy procedures, R2s also remained <60%. Overall, at surgery, in 27 with normal liver function (ICG15 < 10%), R2s exceeded 60% in one, remained at 50% to 60% in five, and <50% in 21, whereas 23 patients except for one with an ICG15 exceeding 10%, had R2s of <50%. The postoperative serum total bilirubin levels in 84% of the patients remained within the normal range and there was no surgery-related mortality. In conclusion, 1) Vol-CT can accurately assess the extent of liver resection, 2) individuals with normal liver function can undergo resection of up to 60% of the nontumorous parenchyma without the need for PE, and 3) PE can be used to reduce the size of the resected tissue and increase the volume of the remnant liver to approximate the target limits in individuals with large tumors or minimally abnormal liver function.
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