Xenografted Human Amniotic Membrane–Derived Mesenchymal Stem Cells Are Immunologically Tolerated and Transdifferentiated Into Cardiomyocytes

Abstract

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...

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