Comparative investigation of host immune response, graft survival and in vivo differentiation after transplantation of undifferentiated embryonic stem cells (ESCs), ESC-derived mesendodermal cardiomyocyte precursors and ESC-derived cardiomyocytes in a mou

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Major limitations for the therapeutic use of embryonic stem cells (ESCs) include the lack of availability of autologous ESCs and their tumorigenic potential. Although recent reports demonstrated low immunogenicity of ESCs and long term survival of allogeneic ESC transplants without any immunosuppression, transplantation of more differentiated cardiomyogenic ESC progeny may be advantageous not only from a functional point of view, since clinical application of undifferentiated ESCs would be associated with the risk for teratoma formation. With respect to future clinical application, it is the goal of the present project to comparatively investigate the immunogenicity and regenerative potential of ESCs and their more mature (and less tumorigenic) cardiomyogenic derivates. To achieve this, undifferentiated ESCs, ESC-derived mesendodermal precursors and more mature ESC-derived cardiomyocytes will be transplanted intramyocardially in a mouse model of myocardial ischemia and will be tested for their allostimulatory potential in vitro. Survival, engraftment and in vivo differentiation of donor ESC cells and their derivates will be evaluated at various time points following cell transplantation with various levels of Major Histocompatibility (MHC) mismatch not only to discriminate cell death related unspecific and allograft-specific immune responses, but also to compare regenerative effects of the applied cell types. We hypothesize that ESC-derived mesendodermal progenitors may be superior compared to undifferentiated ESCs and mature cardiomyocytes with respect to low tumorgenicity, low immunogenicity and high regenerative potential. We expect the resulting insights to significantly contribute to the design of clinical cell transplantation protocols in myocardial restoration.