Modeling of Friedreich ataxia-related iron overloading cardiomyopathy using patient-specific-induced pluripotent stem cells

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• 作者：Yee-Ki Lee (1)
  Philip Wing-Lok Ho (2)
  Revital Schick (3) (4) (5)
  Yee-Man Lau (1)
  Wing-Hon Lai (1)
  Ting Zhou (6)
  Yanhua Li (6)
  Kwong-Man Ng (1)
  Shu-Leung HO (2)
  Miguel Angel Esteban (6)
  Ofer Binah (3) (4) (5)
  Hung-Fat Tse (1)
  Chung-Wah Siu (1) (7)
  
• 关键词：Friedreich ataxia ; Induced pluripotent stem cells ; Cardiomyopathy
• 刊名：Pfl篓鹿gers Archiv - European Journal of Physiology
• 出版年：2014
• 出版时间：September 2014
• 年：2014
• 卷：466
• 期：9
• 页码：1831-1844
• 全文大小：2,402 KB
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• 作者单位：Yee-Ki Lee (1)
  Philip Wing-Lok Ho (2)
  Revital Schick (3) (4) (5)
  Yee-Man Lau (1)
  Wing-Hon Lai (1)
  Ting Zhou (6)
  Yanhua Li (6)
  Kwong-Man Ng (1)
  Shu-Leung HO (2)
  Miguel Angel Esteban (6)
  Ofer Binah (3) (4) (5)
  Hung-Fat Tse (1)
  Chung-Wah Siu (1) (7)
  
  1. Cardiology Division, Department of Medicine, Li Ka Shing Faculty of Medicine, the University of Hong Kong, Hong Kong, China
  2. Neurology Division, Department of Medicine, Li Ka Shing Faculty of Medicine, the University of Hong Kong, Hong Kong, China
  3. Department of Physiology, The Sohnis Family Stem Cells Center, Technion - Israel Institute of Technology, Haifa, Israel
  4. Department of Physiology, The Rappaport Family Institute for Research in the Medical Sciences, Technion - Israel Institute of Technology, Haifa, Israel
  5. Department of Physiology, Ruth & Bruce Rappaport Faculty of Medicine, Technion - Israel Institute of Technology, Haifa, Israel
  6. Stem Cell and Cancer Biology Group, Key Laboratory of Regenerative Biology, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China
  7. Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Rm 1929A, Block K, Hong Kong, China
  
• ISSN：1432-2013

文摘

Friedreich ataxia (FRDA), a recessive neurodegenerative disorder commonly associated with hypertrophic cardiomyopathy, is due to GAA repeat expansions within the first intron of the frataxin (FXN) gene encoding the mitochondrial protein involved in iron–sulfur cluster biosynthesis. The triplet codon repeats lead to heterochromatin-mediated gene silencing and loss of frataxin. Nevertheless, inadequacy of existing FRDA-cardiac cellular models limited cardiomyopathy studies. We tested the hypothesis that iron homeostasis deregulation accelerates reduction in energy synthesis dynamics which contributes to impaired cardiac calcium homeostasis and contractile force. Silencing of FXN expressions occurred both in somatic FRDA-skin fibroblasts and two of the induced pluripotent stem cells (iPSC) clones; a sign of stress condition was shown in FRDA-iPSC cardiomyocytes with disorganized mitochondrial network and mitochondrial DNA (mtDNA) depletion; hypertrophic cardiac stress responses were observed by an increase in α-actinin-positive cell sizes revealed by FACS analysis as well as elevation in brain natriuretic peptide (BNP) gene expression; the intracellular iron accumulated in FRDA cardiomyocytes might be due to attenuated negative feedback response of transferring receptor (TSFR) expression and positive feedback response of ferritin (FTH1); energy synthesis dynamics, in terms of ATP production rate, was impaired in FRDA-iPSC cardiomyocytes, which were prone to iron overload condition. Energetic insufficiency determined slower Ca2+ transients by retarding calcium reuptake to sarcoplasmic reticulum (SR) and impaired the positive inotropic and chronotropic responses to adrenergic stimulation. Our data showed for the first time that FRDA-iPSCs cardiac derivatives represent promising models to study cardiac stress response due to impaired iron homeostasis condition and mitochondrial damages. The cardiomyopathy phenotype was accelerated in an iron-overloaded condition early in calcium homeostasis aspect.