Modeling inherited cardiac diseases with iPS-derived engineered heart tissue

目前治疗心力衰竭和心律失常的方法已经提高了存活率，但新的概念尽管在动物身上提供了令人印象深刻的好处，但最近却失败了，这表明临床前模型的预测价值很低，“人人共享”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极大关注。它们在伦理上是非关键的，可以从患者的S体细胞中分离出来，分化成所需的细胞类型，用于再生治疗和体外测试系统。原则战略是直截了当的，但关键问题尚未解决。(1)iPS向心肌细胞分化是无效的、非定向的。该项目采用了一种新的前向规划策略来强制差异化，并采用了无偏见的方法来确定控制差异化的新因素。(2)先验的前提是，在“人类情境”中进行测试会使结果更具预测性。然而，由于几个原因，这一承诺仍未实现，包括将皮肤细胞转变为心肌细胞所需的大量操作，iPS来源的心肌细胞的不成熟表型，以及缺乏良好的体外模型。PI开创了从具有完整心肌高级特征的原代和人类胚胎干细胞产生自发跳动、力量发展的3D工程心脏组织(EHT)的技术，最近推出了一个新的EHTPlatform，提供力量、频率和节律的全自动分析。假设iPS-EHT在体外充分发挥iPS的潜力来评估疾病特异性机制和新的治疗干预措施。该项目可以带来个性化的治疗概念，并具有推动再生治疗发展的前景。

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.