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Research Paper|Volume 9, Issue 5|pp 1440—1452

Friedreich’s ataxia induced pluripotent stem cell-derived cardiomyocytes display electrophysiological abnormalities and calcium handling deficiency

Duncan E. Crombie1,2, Claire L. Curl3, Antonia JA Raaijmakers3, Priyadharshini Sivakumaran4, Tejal Kulkarni1,2,5, Raymond CB Wong1,2, Itsunari Minami6, Marguerite V. Evans-Galea7, Shiang Y. Lim2,4, Lea Delbridge4, Louise A. Corben7,8, Mirella Dottori5, Norio Nakatsuji6, Ian A. Trounce1,2, Alex W. Hewitt1,2,9, Martin B. Delatycki7,8,10, Martin F. Pera11, Alice Pébay1,2
  • 1Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, Melbourne, Australia
  • 2Ophthalmology, Department of Surgery, the University of Melbourne, Melbourne, Australia
  • 3Department of Physiology, the University of Melbourne, Melbourne, Australia
  • 4O’Brien Institute Department, St Vincent Institute of Medical Research, Fitzroy, Australia
  • 5Centre for Neural Engineering & Department of Electrical and Electronic Engineering, The University of Melbourne, Melbourne, Australia
  • 6Institute for Integrated Cell-Material Sciences, Kyoto University, Kyoto, Japan
  • 7Bruce Lefroy Centre for Genetic Health Research, Murdoch Children’s Research Institute, & Department of Paediatrics, The University of Melbourne, Melbourne, Australia
  • 8School of Psychological Sciences, Monash University, Frankston, Australia
  • 9Menzies Institute for Medical Research, School of Medicine, University of Tasmania, Hobart, Australia
  • 10Victorian Clinical Genetics Services, Parkville, Australia
  • 11Department of Anatomy and Neurosciences, the University of Melbourne, Florey Neuroscience & Mental Health Institute, Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia
Received: April 26, 2017Accepted: May 27, 2017Published: May 30, 2017

Copyright: © 2017 Crombie et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

We sought to identify the impacts of Friedreich’s ataxia (FRDA) on cardiomyocytes. FRDA is an autosomal recessive degenerative condition with neuronal and non-neuronal manifestations, the latter including progressive cardiomyopathy of the left ventricle, the leading cause of death in FRDA. Little is known about the cellular pathogenesis of FRDA in cardiomyocytes. Induced pluripotent stem cells (iPSCs) were derived from three FRDA individuals with characterized GAA repeats. The cells were differentiated into cardiomyocytes to assess phenotypes. FRDA iPSC- cardiomyocytes retained low levels of FRATAXIN (FXN) mRNA and protein. Electrophysiology revealed an increased variation of FRDA- cardiomyocyte beating rates which was prevented by addition of nifedipine, suggestive of a calcium handling deficiency. Finally, calcium imaging was performed and we identified small amplitude, diastolic and systolic calcium transients confirming a deficiency in calcium handling. We defined a robust FRDA cardiac-specific electrophysiological profile in patient-derived iPSCs which could be used for high throughput compound screening. This cell-specific signature will contribute to the identification and screening of novel treatments for this life-threatening disease.