Modeling inherited cardiac diseases with iPS-derived engineered heart tissue

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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.