Key Words: cardiomyogenesis Ⅲ human mesenchymal stem cell Ⅲ immunologic tolerance Ⅲ myocardial infarction Ⅲ cell-based therapy A lthough embryonic stem cells 1 and induced pluripotent stem (iPS) cells 2 can be differentiated into cells of various organs, including cardiomyocytes, there are many underlining problems to overcome before clinical applications can be used, eg, tumorigenicity. 3 Autografts of iPS cells may not cause immunologic rejection; ironically, however, possible neoplasm formation would cause a serious problem because the neoplasm would not be rejected by the withdrawal of immunosuppressive agents. On the other hand, mesenchymal stem cells (MSCs) have recently been used for clinical application, and their safety and feasibility in cardiac stem cell-based therapy have been demonstrated. 4 Thus, MSCs are a more important cellular source for stem cell-based therapy from a practical point of view.The efficacy of human bone marrow-derived MSCs (BMMSCs) was still limited, 5 however, because of low efficiency for cardiomyogenic transdifferentiation. 6 We previously reported that non-marrow-derived mesenchymal cells had higher cardiomyogenic transdifferentiation efficiency, eg, menstrual blood-derived mesenchymal cells (MMCs), 7 umbilical cord blood-derived mesenchymal stem cells (UCB-MSCs), 8 and placental chorionic plate-derived mesenchymal cells (PCPCs). 9 These cells are thought to be used by an allograft; therefore, problems of immunologic rejection arise. However, an allograft may be superior to an autograft in several ways. Taking into account the background condition of the patient (eg, metabolic disease or age), Original received July 16, 2009; revision received April 14, 2010; accepted April 22, 2010 16 reported significant recovery of cardiac function by the rat amnion-derived cell transplantation in rat myocardial infarction (MI) model, however, they failed to show clear evidence of cardiomyogenic differentiation in vivo. Therefore, in the present study, we attempted to show: (1) the powerful cardiomyogenic transdifferentiation potential of our isolated hAMCs, and the beneficial effect of transplantation of hAMCs on cardiac function in vivo; (2) the induction of immunologic tolerance so that hAMCs can be a powerful allograftable stem cell source without either the administration of immunosuppressive agents or matching of MHC typing; (3) the mechanism of induction of tolerance; and (4) the close relationship between the cardiomyogenic transdifferentiation of mesenchymal cells and the process of immunologic tolerance. MethodsAn expanded Methods section is available in the Online Data Supplement at http://circres.ahajournals.org. Isolation and Culture of Human Amniotic Membrane-Derived Mesenchymal CellsHuman amniotic membrane was collected, with informed consent from individual patients, after delivery of a male neonate. The study was approved by the ethics committee of Keio University School of Medicine. The precise methods for culture have been described previously. 9,17 Detail is shown in...

The efficacy of transplantation of default human marrowderived mesenchymal stem cells (MSCs) was modest. In this study, our challenge was to improve the efficacy of MSC transplantation in vivo by pretreatment of MSCs with pioglitazone. MSCs were cultured with or without medium containing 1 lM of pioglitazone before cardiomyogenic induction. After cardiomyogenic induction in vitro, cardiomyogenic transdifferentiation efficiency (CTE) was calculated by immunocytochemistry using anti-cardiac troponin-I antibody. For the in vivo experiments, myocardial infarction (MI) at the anterior left ventricle was made in nude rats. Two weeks after MI, MSCs pretreated with pioglitazone (p-BM; n 5 30) or without pioglitazone (BM; n 5 17) were injected, and then survived for 2 weeks. We compared left ventricular function by echocardiogram and immunohistochemistry to observe cardiomyogenic transdifferentiation in vivo. Pretreatment with pioglitazone significantly increased the CTE in vitro (1.9% 6 0.2% n 5 47 vs. 39.5% 6 4.7% n 5 13, p < .05). Transplantation of pioglitazone pretreated MSCs significantly improved change in left ventricular % fractional shortening (BM; 24.8% 6 2.1%, vs. p-BM; 5.2% 6 1.5%). Immunohistochemistry revealed significant improvement of cardiomyogenic transdifferentiation in p-BM in vivo (BM; 0% 6 0% n 5 5, vs. p-BM; 0.077% 6 0.041% n 5 5). Transplantation of pioglitazonepretreated MSCs significantly improved cardiac function and can be a promising cardiac stem cell source to expect cardiomyogenesis.

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Background: His-bundle pacing (HBP) is a physiological form of pacing. Although high capture thresholds are common, few predictors of low HBP threshold have been determined. We aimed to identify electrophysiological predictors. Methods: Fifty-one patients (53% with atrioventricular block) underwent HBP for bradycardia with an intrinsic QRS duration of <120 ms. Attempts to anchor the HBP lead were guided by unipolar His-bundle electrograms (HB EGMs) recorded with an electrophysiology recording system. Patients were followed-up for >6 months. Results: In total, 153 attempts at anchoring the HBP lead were made, of which, 45 achieved acceptable HBP thresholds (≤2.5 V at 1 ms). The amplitude of negative deflection in HB EGM and the selective HBP form at fixation were independently associated with achieving an acceptable threshold. A negative amplitude of ≥0.060 mV in HB EGM was determined as the optimal value for identifying the acceptable threshold. This deep negative HB EGM was recorded with an HBP threshold of 1.4±1.3 V (in 34 attempts), significantly lower than that of positive HB EGM without deep negative deflection (2.8±1.3 V, in 31 trials; or >5 V, in 38 trials). The permanent HBP lead remained with deep negative (≥0.060 mV) or positive HB EGMs in 28 and 14 patients, respectively, and with positive or negative HB injury current in 19 and 23 patients, respectively. During follow-up, increased HBP threshold of >1 V was significantly more prevalent in the positive HB EGM group. The HBP thresholds of deep negative HB EGM and HB injury current, but not of the selective HBP group, were significantly lower than the other subgroups during follow-up. Conclusions: Deep negative HB EGM at fixation was associated with an excellent short-term HBP threshold, similar to HB injury current. Analysis of unipolar HB EGM postfixation may enable prediction of permanent HBP threshold.