Modeling inherited cardiac diseases with iPS-derived engineered heart tissue

目前心力衰竭和心律失常的治疗提高了生存率，但新概念尽管在动物中提供了令人印象深刻的益处，但最近失败了，这表明临床前模型的预测价值很低，“一个为所有”的方法可能是错误的。在这种背景下，诱导多能干细胞（iPS）的建立引起了公众的极大关注。它们在伦理上是不重要的，可以来自患者的体细胞，分化成所需的细胞类型，并用于再生疗法和体外测试系统。主要战略是直截了当的，但关键问题尚未解决。(1)从iPS分化心肌细胞是无效和无定向的。该项目采用了一种新的前向规划策略，迫使分化和公正的方法，以确定新的因素控制分化。(2)先验的前提是，在“人类环境”中进行测试使结果更具预测性。然而，由于几个原因，这一承诺尚未实现，包括将皮肤细胞转化为肌细胞所需的众多操作，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开创了从原代和人类胚胎干细胞中产生自发跳动、力发展的3D工程心脏组织（EHT）的技术，该组织具有完整心肌的先进特征，最近还开发了一个新的EHT平台，可提供力、频率和节律的全自动分析。假设iPS-EHT开发了iPS的全部潜力，以评估疾病特异性机制和新的体外治疗干预措施。该项目可能会导致个性化治疗的概念，并有前景，以促进再生疗法的发展。

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.