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Studying arrhythmogenic right ventricular dysplasia with patient-specific iPSCs

2013; Nature Portfolio; Volume: 494; Issue: 7435 Linguagem: Inglês

10.1038/nature11799

1476-4687

Changsung Kim, Johnson Wong, Jianyan Wen, Shirong Wang, Cheng Wang, Sean Spiering, Natalia G. Kan, Sonia Vanina Forcales, Prem Puri, Teresa C. Leone, Joseph E. Marine, Hugh Calkins, Daniel P. Kelly, Daniel P. Judge, Huei-Sheng Vincent Chen,

Radiation Effects in Electronics

This study demonstrates that an inheritable adult onset heart disease can be modelled in vitro within months with the help of metabolic maturation induction. Recent advances in cellular reprogramming of fibroblasts as patient-specific induced pluripotent stem cells (iPSCs) have made it possible to model genetic disorders in vitro. But for adult-onset conditions, tissues derived from iPSCs or stem cells, such as cardiomyocytes or neurons, tend to 'reset' to an embryo-like state, losing the disease characteristic that emerged after a period of latency. This study demonstrates that an inheritable adult-onset disease can be modelled within months. The authors used patient-specific iPSCs with a plakophilin-2 mutation to model arrhythmogenic right ventricular dysplasia/cardiomyopathy. Typical pathology was not evident at first, but emerged within 2 months when adult-like energy metabolism was induced using a 5-factor protocol. Cellular reprogramming of somatic cells to patient-specific induced pluripotent stem cells (iPSCs) enables in vitro modelling of human genetic disorders for pathogenic investigations and therapeutic screens1,2,3,4,5,6,7. However, using iPSC-derived cardiomyocytes (iPSC-CMs) to model an adult-onset heart disease remains challenging owing to the uncertainty regarding the ability of relatively immature iPSC-CMs to fully recapitulate adult disease phenotypes. Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) is an inherited heart disease characterized by pathological fatty infiltration and cardiomyocyte loss predominantly in the right ventricle8, which is associated with life-threatening ventricular arrhythmias. Over 50% of affected individuals have desmosome gene mutations, most commonly in PKP2, encoding plakophilin-2 (ref. 9). The median age at presentation of ARVD/C is 26 years8. We used previously published methods1,10 to generate iPSC lines from fibroblasts of two patients with ARVD/C and PKP2 mutations11,12. Mutant PKP2 iPSC-CMs demonstrate abnormal plakoglobin nuclear translocation and decreased β-catenin activity13 in cardiogenic conditions; yet, these abnormal features are insufficient to reproduce the pathological phenotypes of ARVD/C in standard cardiogenic conditions. Here we show that induction of adult-like metabolic energetics from an embryonic/glycolytic state and abnormal peroxisome proliferator-activated receptor gamma (PPAR-γ) activation underlie the pathogenesis of ARVD/C. By co-activating normal PPAR-alpha-dependent metabolism and abnormal PPAR-γ pathway in beating embryoid bodies (EBs) with defined media, we established an efficient ARVD/C in vitro model within 2 months. This model manifests exaggerated lipogenesis and apoptosis in mutant PKP2 iPSC-CMs. iPSC-CMs with a homozygous PKP2 mutation also had calcium-handling deficits. Our study is the first to demonstrate that induction of adult-like metabolism has a critical role in establishing an adult-onset disease model using patient-specific iPSCs. Using this model, we revealed crucial pathogenic insights that metabolic derangement in adult-like metabolic milieu underlies ARVD/C pathologies, enabling us to propose novel disease-modifying therapeutic strategies.