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

Authors

Duncan E. Crombie, Royal Victorian Eye and Ear Hospital, University of Melbourne
Claire L. Curl, University of Melbourne
Antonia J.A Raaijmakers, University of Melbourne
Priyadharshini Sivakumaran, St Vincents Institute of Medical Research
Tejal Kulkarni, Royal Victorian Eye and Ear Hospital, University of Melbourne
Raymond C. B Wong, Royal Victorian Eye and Ear Hospital, University of Melbourne
Itsunari Minami, Kyoto University
Marguerite V. Evans-Galea, University of Melbourne, Murdoch Children's Research Institute
Shiang Y. Lim, St Vincents Institute of Medical Research, University of Melbourne
Lea M. D Delbridge, St Vincent Institute of Medical ResearchFollow
Louise A. Corben, University of Melbourne, Murdoch Children's Research Institute, Monash University
Mirella Dottori, University of MelbourneFollow
Norio Nakatsuji, Kyoto University
Ian A. Trounce, University of Melbourne, Royal Victorian Eye and Ear Hospital
Alex W. Hewitt, Royal Victorian Eye and Ear Hospital, University of Tasmania, University of Melbourne
Martin B. Delatycki, Monash University, Victorian Clinical Genetics Services, University of Melbourne, Murdoch Children's Research Institute
Martin F. Pera, University of Melbourne, The Walter & Eliza Hall Institute of Medical Research, Florey Institute of Neuroscience and Mental Health
Alice Pebay, University of Melbourne, Royal Victorian Eye and Ear Hospital

RIS ID

117742

Publication Details

Crombie, D. E., Curl, C. L., Raaijmakers, A. J. A., Sivakumaran, P., Kulkarni, T., Wong, R. C. B., Minami, I., Evans-Galea, M. V., Lim, S. Y., Delbridge, L., Corben, L. A., Dottori, M., Nakatsuji, N., Trounce, I. A., Hewitt, A. W., Delatycki, M. B., Pera, M. F. & Pebay, A. (2017). Friedreich's ataxia induced pluripotent stem cell-derived cardiomyocytes display electrophysiological abnormalities and calcium handling deficiency. Aging, 9 (5), 1440-1452.

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.