Enhanced β-adrenergic signaling and higher sensitivity to catecholamine-induced toxicity were identified as mechanisms associated with the TTS phenotype. (International Takotsubo Registry [InterTAK Registry] [InterTAK]; NCT01947621).

Non-human primates (NHP) are important surrogate models for late preclinical development of advanced therapy medicinal products (ATMPs), including induced pluripotent stem cell (iPSC)-based therapies, which are also under development for heart failure repair. For effective heart repair by remuscularization, large numbers of cardiomyocytes are required, which can be obtained by efficient differentiation of iPSCs. However, NHP-iPSC generation and long-term culture in an undifferentiated state under feeder cell-free conditions turned out to be problematic. Here we describe the reproducible development of rhesus macaque (Macaca mulatta) iPSC lines. Postnatal rhesus skin fibroblasts were reprogrammed under chemically defined conditions using non-integrating vectors. The robustness of the protocol was confirmed using another NHP species, the olive baboon (Papio anubis). Feeder-free maintenance of NHP-iPSCs was essentially dependent on concurrent Wnt-activation by GSK-inhibition (Gi) and Wnt-inhibition (Wi). Generated NHP-iPSCs were successfully differentiated into cardiomyocytes using a combined growth factor/GiWi protocol. The capacity of the iPSC-derived cardiomyocytes to self-organize into contractile engineered heart muscle (EHM) was demonstrated. Collectively, this study establishes a reproducible protocol for the robust generation and culture of NHP-iPSCs, which are useful for preclinical testing of strategies for cell replacement therapies in NHP.

Heart disease is the principal cause of death in humans. Stem cell-based therapy for heart regeneration has long been seen as a potential application since the heart lacks adequate intrinsic regenerative potential. In the cardiovascular field, clinical trials have already been carried out by implantation of both bone marrow-derived stem cells and cardiac resident progenitor cells derived from the adult heart tissue into the injured myocardium to restore the functionality of the heart after damage. However, before a robust stem and progenitor cell-based therapy for cardiovascular diseases can be applied in the clinical setting, more research is necessary to generate sufficient quantities of functional cardiomyocytes from stem cells and to understand behavior of cardiomyocytes upon transplantation. A comprehensive understanding of the developmental processes involved in cardiogenesis might support further investigations in more efficient cell-based regeneration therapies. This review discusses the molecular aspects of cardiogenesis during early development and links the insights with the in vitro generation of cardiac progenitor cells as well as functional cardiomyocytes. Furthermore, we discuss the advantages of cardiac progenitor cells and cardiomyocytes derived from pluripotent stem cells, cardiac resident stem cells in regenerative applications to cope with the damaged heart.