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Modeling inherited cardiac diseases with iPS-derived engineered heart tissue

利用 iPS 衍生的工程心脏组织模拟心脏遗传性疾病

基本信息

批准号：
189427989
负责人：
Professor Dr. Thomas Eschenhagen
金额：
--
依托单位：
Institut für Experimentelle Pharmakologie und Toxikologie
依托单位国家：
德国
项目类别：
Research Grants
财政年份：
2011
资助国家：
德国
起止时间：
2010-12-31 至 2014-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/189427989?language=en
关键词：
Modeling inherited cardiac diseases iPS

项目摘要

Current therapy of heart failure and arrhythmias has improved survival, but new concepts, despite providing impressive benefits in animals, have recently failed, indicating that the predictive value of preclinical models is low and the “one for all” approach may be wrong. In this context the establishment of induced pluripotent stem cells (iPS) stirred enormous public attention. They are ethically uncritical, can be derived from a patient´s somatic cell, differentiated into the desired cell type and used for regenerative therapies and in vitro test systems. The principle strategy is straightforward, but key issues are unresolved. (1) Differentiation of cardiac myocytes from iPS is ineffective and undirected. The project employs a novel forward programming strategy to force differentiation and unbiased approaches to identify new factors controlling differentiation. (2) The a priori premise is that testing in a “human context” makes results more predictive. However, this promise is yet unfulfilled for several reasons, including the numerous maneuvers required to turn a skin cell into a myocyte, the immature phenotype of iPS-derived myocytes and the lack of good in vitro models. The PIs have pioneered techniques to generate spontaneously beating, force-developing 3D engineered heart tissues (EHT) from primary and human embryonic stem cells with advanced features of intact heart muscle and a recent novel EHTplatform providing fully automated analyses of force, frequency and rhythm. The hypothesis is that iPS-EHT develop the full potential of iPS to evaluate disease-specific mechanisms and new therapeutic interventions in vitro. The project could lead to individualized therapy concepts and has the perspective to advance the development of regenerative therapies.

目前心力衰竭和心律失常的治疗方法提高了生存率，但新概念尽管在动物身上提供了令人印象深刻的益处，但最近却失败了，这表明临床前模型的预测价值很低，“一刀切”的方法可能是错误的。在此背景下，诱导多能干细胞（iPS）的建立引起了公众的广泛关注。它们在伦理上没有批判性，可以从患者的体细胞中提取，分化成所需的细胞类型，并用于再生疗法和体外测试系统。原则策略很简单，但关键问题尚未解决。 (1) iPS对心肌细胞的分化是无效且无定向的。该项目采用新颖的前向编程策略来强制分化，并采用公正的方法来识别控制分化的新因素。 (2) 先验前提是在“人类环境”中进行测试使结果更具预测性。然而，由于多种原因，这一承诺尚未实现，包括将皮肤细胞转化为肌细胞所需的大量操作、iPS 衍生的肌细胞的不成熟表型以及缺乏良好的体外模型。 PI 开创了利用原代胚胎干细胞和人类胚胎干细胞生成自发跳动、产生力量的 3D 工程心脏组织 (EHT) 的技术，该心脏组织具有完整心肌的先进特征，并且最近的新型 EHT 平台可提供力量、频率和节律的全自动分析。假设 iPS-EHT 充分发挥 iPS 的潜力来评估疾病特异性机制和体外新的治疗干预措施。该项目可能会带来个体化治疗概念，并有望推动再生疗法的发展。