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

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. Litt...

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Autores principales: Crombie, Duncan E., Curl, Claire L., Raaijmakers, Antonia JA, Sivakumaran, Priyadharshini, Kulkarni, Tejal, Wong, Raymond CB, Minami, Itsunari, Evans-Galea, Marguerite V., Lim, Shiang Y., Delbridge, Lea, Corben, Louise A., Dottori, Mirella, Nakatsuji, Norio, Trounce, Ian A., Hewitt, Alex W., Delatycki, Martin B., Pera, Martin F., Pébay, Alice
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Impact Journals LLC 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5472743/
https://www.ncbi.nlm.nih.gov/pubmed/28562313
http://dx.doi.org/10.18632/aging.101247
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author Crombie, Duncan E.
Curl, Claire L.
Raaijmakers, Antonia JA
Sivakumaran, Priyadharshini
Kulkarni, Tejal
Wong, Raymond CB
Minami, Itsunari
Evans-Galea, Marguerite V.
Lim, Shiang Y.
Delbridge, Lea
Corben, Louise A.
Dottori, Mirella
Nakatsuji, Norio
Trounce, Ian A.
Hewitt, Alex W.
Delatycki, Martin B.
Pera, Martin F.
Pébay, Alice
author_facet Crombie, Duncan E.
Curl, Claire L.
Raaijmakers, Antonia JA
Sivakumaran, Priyadharshini
Kulkarni, Tejal
Wong, Raymond CB
Minami, Itsunari
Evans-Galea, Marguerite V.
Lim, Shiang Y.
Delbridge, Lea
Corben, Louise A.
Dottori, Mirella
Nakatsuji, Norio
Trounce, Ian A.
Hewitt, Alex W.
Delatycki, Martin B.
Pera, Martin F.
Pébay, Alice
author_sort Crombie, Duncan E.
collection PubMed
description 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.
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spelling pubmed-54727432017-06-28 Friedreich's ataxia induced pluripotent stem cell-derived cardiomyocytes display electrophysiological abnormalities and calcium handling deficiency Crombie, Duncan E. Curl, Claire L. Raaijmakers, Antonia JA Sivakumaran, Priyadharshini Kulkarni, Tejal Wong, Raymond CB Minami, Itsunari Evans-Galea, Marguerite V. Lim, Shiang Y. Delbridge, Lea Corben, Louise A. Dottori, Mirella Nakatsuji, Norio Trounce, Ian A. Hewitt, Alex W. Delatycki, Martin B. Pera, Martin F. Pébay, Alice Aging (Albany NY) Research Paper 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. Impact Journals LLC 2017-05-30 /pmc/articles/PMC5472743/ /pubmed/28562313 http://dx.doi.org/10.18632/aging.101247 Text en Copyright: © 2017 Crombie et al. http://creativecommons.org/licenses/by/3.0/ This article is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0/) (CC-BY), which permits unrestricted use and redistribution provided that the original author and source are credited.
spellingShingle Research Paper
Crombie, Duncan E.
Curl, Claire L.
Raaijmakers, Antonia JA
Sivakumaran, Priyadharshini
Kulkarni, Tejal
Wong, Raymond CB
Minami, Itsunari
Evans-Galea, Marguerite V.
Lim, Shiang Y.
Delbridge, Lea
Corben, Louise A.
Dottori, Mirella
Nakatsuji, Norio
Trounce, Ian A.
Hewitt, Alex W.
Delatycki, Martin B.
Pera, Martin F.
Pébay, Alice
Friedreich's ataxia induced pluripotent stem cell-derived cardiomyocytes display electrophysiological abnormalities and calcium handling deficiency
title Friedreich's ataxia induced pluripotent stem cell-derived cardiomyocytes display electrophysiological abnormalities and calcium handling deficiency
title_full Friedreich's ataxia induced pluripotent stem cell-derived cardiomyocytes display electrophysiological abnormalities and calcium handling deficiency
title_fullStr Friedreich's ataxia induced pluripotent stem cell-derived cardiomyocytes display electrophysiological abnormalities and calcium handling deficiency
title_full_unstemmed Friedreich's ataxia induced pluripotent stem cell-derived cardiomyocytes display electrophysiological abnormalities and calcium handling deficiency
title_short Friedreich's ataxia induced pluripotent stem cell-derived cardiomyocytes display electrophysiological abnormalities and calcium handling deficiency
title_sort friedreich's ataxia induced pluripotent stem cell-derived cardiomyocytes display electrophysiological abnormalities and calcium handling deficiency
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5472743/
https://www.ncbi.nlm.nih.gov/pubmed/28562313
http://dx.doi.org/10.18632/aging.101247
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