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

小鼠中移植未分化胚胎干细胞（ESC）、ESC衍生的中内胚层心肌细胞前体和ESC衍生的心肌细胞后宿主免疫反应、移植物存活和体内分化的比较研究

• 批准号: 34282297
• 负责人: Professor Dr. Ulrich Martin
• 金额: --
• 依托单位: Klinik für Allgemein-, Viszeral- und Transplantationschirurgie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2007
• 资助国家: 德国
• 起止时间: 2006-12-31 至 2010-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/34282297?language=en
• 关键词: Comparative; investigation; host; immune; response

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.

胚胎干细胞(ESCs)治疗应用的主要限制包括缺乏自体ESCs及其致瘤潜力。虽然最近的报道显示胚胎干细胞的免疫原性低，同种异体胚胎干细胞移植在没有任何免疫抑制的情况下可以长期存活，但从功能角度来看，移植分化更多的心肌来源的胚胎干细胞后代可能是有利的，因为临床应用未分化的胚胎干细胞会增加畸胎瘤的形成风险。关于未来的临床应用，本项目的目标是比较研究ESCs及其更成熟(和较少致瘤)的心肌衍生物的免疫原性和再生潜力。为了实现这一目标，未分化的ESCs、ESC来源的中内胚层前体细胞和更成熟的ESC来源的心肌细胞将被移植到心肌缺血小鼠的心肌内，并将在体外测试它们的同种异体刺激潜力。在不同主要组织相容性(MHC)不匹配的细胞移植后的不同时间点，将对供体ESC细胞及其衍生细胞的存活、植入和体内分化进行评估，不仅为了区分细胞死亡相关的非特异性免疫反应和同种异体移植特异性免疫反应，还为了比较所应用细胞类型的再生效果。我们推测，与未分化的ESCs和成熟的心肌细胞相比，ESC来源的中内胚层前体细胞在低致瘤性、低免疫原性和高再生潜力方面可能更优越。我们期望由此产生的洞察力对设计心肌修复的临床细胞移植方案有很大的帮助。