Publication Date:
2013-01-29
Description:
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 beta-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-gamma) activation underlie the pathogenesis of ARVD/C. By co-activating normal PPAR-alpha-dependent metabolism and abnormal PPAR-gamma 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.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3753229/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3753229/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉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 -- R01 AR052779/AR/NIAMS NIH HHS/ -- R01 AR056712/AR/NIAMS NIH HHS/ -- R01 HL058493/HL/NHLBI NIH HHS/ -- R01 HL101189/HL/NHLBI NIH HHS/ -- R01 HL105194/HL/NHLBI NIH HHS/ -- TCR05004/Telethon/Italy -- England -- Nature. 2013 Feb 7;494(7435):105-10. doi: 10.1038/nature11799. Epub 2013 Jan 27.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Del E. Webb Neuroscience, Aging & Stem Cell Research Center, Sanford-Burnham Medical Research Institute, La Jolla, California 92037, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23354045" target="_blank"〉PubMed〈/a〉
Keywords:
Active Transport, Cell Nucleus
;
Age of Onset
;
Apoptosis/genetics
;
Arrhythmogenic Right Ventricular
;
Dysplasia/genetics/*metabolism/*pathology/physiopathology
;
Cellular Reprogramming
;
Culture Media/pharmacology
;
Embryoid Bodies/drug effects/physiology
;
Energy Metabolism/genetics
;
Fatty Acids/metabolism
;
Fibroblasts/metabolism/pathology
;
Glucose/metabolism
;
Glycolysis
;
Humans
;
Induced Pluripotent Stem Cells/metabolism/*pathology
;
Lipogenesis/genetics
;
*Models, Biological
;
Myocardial Contraction/drug effects
;
Myocytes, Cardiac/pathology
;
PPAR alpha/metabolism
;
PPAR gamma/metabolism
;
Phenotype
;
Plakophilins/genetics
;
Time Factors
;
beta Catenin/metabolism
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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