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

胚胎干细胞（ESC）的治疗用途的主要限制包括缺乏自体ESC的可用性和它们的致瘤潜力。尽管最近的报道表明ESC的低免疫原性和同种异体ESC移植的长期存活而没有任何免疫抑制，但移植更分化的心肌源性ESC后代可能不仅从功能的角度来看是有利的，因为未分化的ESC的临床应用将与畸胎瘤形成的风险相关。关于未来的临床应用，本项目的目标是比较研究ESC及其更成熟（且致瘤性更低）的心肌衍生物的免疫原性和再生潜力。为了实现这一点，未分化的ESC、ESC衍生的中内胚层前体细胞和更成熟的ESC衍生的心肌细胞将被移植到心肌缺血的小鼠模型中的心肌内，并将在体外测试它们的同种异体刺激潜力。将在具有各种水平的主要组织相容性（MHC）错配的细胞移植后的不同时间点评价供体ESC细胞及其衍生物的存活、植入和体内分化，不仅为了区分细胞死亡相关的非特异性和同种异体移植物特异性免疫应答，而且为了比较所应用的细胞类型的再生效果。我们推测，胚胎干细胞来源的中内胚层祖细胞可能是上级相比，未分化的胚胎干细胞和成熟的心肌细胞的低致瘤性，低免疫原性和高再生潜力。我们期望由此产生的见解，显着有助于心肌修复的临床细胞移植方案的设计。

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.