Studying arrhythmogenic right ventricular dysplasia with patient-specific iPSCs

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

Research output: Contribution to journalArticle

262 Citations (Scopus)

Abstract

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 screens. 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 ventricle, 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 years. We used previously published methods to generate iPSC lines from fibroblasts of two patients with ARVD/C and PKP2 mutations. Mutant PKP2 iPSC-CMs demonstrate abnormal plakoglobin nuclear translocation and decreased β-catenin activity 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.

Original languageEnglish (US)
Pages (from-to)105-110
Number of pages6
JournalNature
Volume494
Issue number7435
DOIs
StatePublished - Feb 7 2013
Externally publishedYes

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Arrhythmogenic Right Ventricular Dysplasia
Induced Pluripotent Stem Cells
Peroxisome Proliferator-Activated Receptors
Cardiac Myocytes
Mutation
Heart Diseases
Plakophilins
gamma Catenin
Embryoid Bodies
Phenotype
PPAR alpha
Catenins
Desmosomes
Lipogenesis
Inborn Genetic Diseases
PPAR gamma
Medical Genetics
Uncertainty
Heart Ventricles
Cardiac Arrhythmias

ASJC Scopus subject areas

  • Medicine(all)
  • General

Cite this

Kim, C., Wong, J., Wen, J., Wang, S., Wang, C., Spiering, S., ... Chen, H. S. V. (2013). Studying arrhythmogenic right ventricular dysplasia with patient-specific iPSCs. Nature, 494(7435), 105-110. https://doi.org/10.1038/nature11799

Studying arrhythmogenic right ventricular dysplasia with patient-specific iPSCs. / Kim, Changsung; Wong, Johnson; Wen, Jianyan; Wang, Shirong; Wang, Cheng; Spiering, Sean; Kan, Natalia G.; Forcales, Sonia; Puri, Pier Lorenzo; Leone, Teresa C.; Marine, Joseph E.; Calkins, Hugh; Kelly, Daniel P.; Judge, Daniel P.; Chen, Huei Sheng Vincent.

In: Nature, Vol. 494, No. 7435, 07.02.2013, p. 105-110.

Research output: Contribution to journalArticle

Kim, C, Wong, J, Wen, J, Wang, S, Wang, C, Spiering, S, Kan, NG, Forcales, S, Puri, PL, Leone, TC, Marine, JE, Calkins, H, Kelly, DP, Judge, DP & Chen, HSV 2013, 'Studying arrhythmogenic right ventricular dysplasia with patient-specific iPSCs', Nature, vol. 494, no. 7435, pp. 105-110. https://doi.org/10.1038/nature11799
Kim C, Wong J, Wen J, Wang S, Wang C, Spiering S et al. Studying arrhythmogenic right ventricular dysplasia with patient-specific iPSCs. Nature. 2013 Feb 7;494(7435):105-110. https://doi.org/10.1038/nature11799
Kim, Changsung ; Wong, Johnson ; Wen, Jianyan ; Wang, Shirong ; Wang, Cheng ; Spiering, Sean ; Kan, Natalia G. ; Forcales, Sonia ; Puri, Pier Lorenzo ; Leone, Teresa C. ; Marine, Joseph E. ; Calkins, Hugh ; Kelly, Daniel P. ; Judge, Daniel P. ; Chen, Huei Sheng Vincent. / Studying arrhythmogenic right ventricular dysplasia with patient-specific iPSCs. In: Nature. 2013 ; Vol. 494, No. 7435. pp. 105-110.
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