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Aging (Albany NY). 2017 May 30;9(5):1440-1452. doi: 10.18632/aging.101247.

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

Author information

1
Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, Melbourne, Australia.
2
Ophthalmology, Department of Surgery, the University of Melbourne, Melbourne, Australia.
3
Department of Physiology, the University of Melbourne, Melbourne, Australia.
4
O'Brien Institute Department, St Vincent Institute of Medical Research, Fitzroy, Australia.
5
Centre for Neural Engineering & Department of Electrical and Electronic Engineering, The University of Melbourne, Melbourne, Australia.
6
Institute for Integrated Cell-Material Sciences, Kyoto University, Kyoto, Japan.
7
Bruce Lefroy Centre for Genetic Health Research, Murdoch Children's Research Institute, & Department of Paediatrics, The University of Melbourne, Melbourne, Australia.
8
School of Psychological Sciences, Monash University, Frankston, Australia.
9
Menzies Institute for Medical Research, School of Medicine, University of Tasmania, Hobart, Australia.
10
Victorian Clinical Genetics Services, Parkville, Australia.
11
Department of Anatomy and Neurosciences, the University of Melbourne, Florey Neuroscience & Mental Health Institute, Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia.

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.

KEYWORDS:

Friedreich’s ataxia; cardiomyopathy; induced pluripotent stem cells; modelling

PMID:
28562313
PMCID:
PMC5472743
DOI:
10.18632/aging.101247
[Indexed for MEDLINE]
Free PMC Article

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