Contractile Defect Caused by Mutation in MYBPC3 Revealed under Conditions Optimized for Human PSC-Cardiomyocyte Function

Maximizing baseline function of human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) is essential for their effective application in models of cardiac toxicity and disease. Here, we aimed to identify factors that would promote an adequate level of function to permit robust single-cell contr...

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Autores principales: Birket, Matthew J., Ribeiro, Marcelo C., Kosmidis, Georgios, Ward, Dorien, Leitoguinho, Ana Rita, van de Pol, Vera, Dambrot, Cheryl, Devalla, Harsha D., Davis, Richard P., Mastroberardino, Pier G., Atsma, Douwe E., Passier, Robert, Mummery, Christine L.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cell Press 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4644234/
https://www.ncbi.nlm.nih.gov/pubmed/26489474
http://dx.doi.org/10.1016/j.celrep.2015.09.025
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author Birket, Matthew J.
Ribeiro, Marcelo C.
Kosmidis, Georgios
Ward, Dorien
Leitoguinho, Ana Rita
van de Pol, Vera
Dambrot, Cheryl
Devalla, Harsha D.
Davis, Richard P.
Mastroberardino, Pier G.
Atsma, Douwe E.
Passier, Robert
Mummery, Christine L.
author_facet Birket, Matthew J.
Ribeiro, Marcelo C.
Kosmidis, Georgios
Ward, Dorien
Leitoguinho, Ana Rita
van de Pol, Vera
Dambrot, Cheryl
Devalla, Harsha D.
Davis, Richard P.
Mastroberardino, Pier G.
Atsma, Douwe E.
Passier, Robert
Mummery, Christine L.
author_sort Birket, Matthew J.
collection PubMed
description Maximizing baseline function of human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) is essential for their effective application in models of cardiac toxicity and disease. Here, we aimed to identify factors that would promote an adequate level of function to permit robust single-cell contractility measurements in a human induced pluripotent stem cell (hiPSC) model of hypertrophic cardiomyopathy (HCM). A simple screen revealed the collaborative effects of thyroid hormone, IGF-1 and the glucocorticoid analog dexamethasone on the electrophysiology, bioenergetics, and contractile force generation of hPSC-CMs. In this optimized condition, hiPSC-CMs with mutations in MYBPC3, a gene encoding myosin-binding protein C, which, when mutated, causes HCM, showed significantly lower contractile force generation than controls. This was recapitulated by direct knockdown of MYBPC3 in control hPSC-CMs, supporting a mechanism of haploinsufficiency. Modeling this disease in vitro using human cells is an important step toward identifying therapeutic interventions for HCM.
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spelling pubmed-46442342015-12-08 Contractile Defect Caused by Mutation in MYBPC3 Revealed under Conditions Optimized for Human PSC-Cardiomyocyte Function Birket, Matthew J. Ribeiro, Marcelo C. Kosmidis, Georgios Ward, Dorien Leitoguinho, Ana Rita van de Pol, Vera Dambrot, Cheryl Devalla, Harsha D. Davis, Richard P. Mastroberardino, Pier G. Atsma, Douwe E. Passier, Robert Mummery, Christine L. Cell Rep Article Maximizing baseline function of human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) is essential for their effective application in models of cardiac toxicity and disease. Here, we aimed to identify factors that would promote an adequate level of function to permit robust single-cell contractility measurements in a human induced pluripotent stem cell (hiPSC) model of hypertrophic cardiomyopathy (HCM). A simple screen revealed the collaborative effects of thyroid hormone, IGF-1 and the glucocorticoid analog dexamethasone on the electrophysiology, bioenergetics, and contractile force generation of hPSC-CMs. In this optimized condition, hiPSC-CMs with mutations in MYBPC3, a gene encoding myosin-binding protein C, which, when mutated, causes HCM, showed significantly lower contractile force generation than controls. This was recapitulated by direct knockdown of MYBPC3 in control hPSC-CMs, supporting a mechanism of haploinsufficiency. Modeling this disease in vitro using human cells is an important step toward identifying therapeutic interventions for HCM. Cell Press 2015-10-17 /pmc/articles/PMC4644234/ /pubmed/26489474 http://dx.doi.org/10.1016/j.celrep.2015.09.025 Text en © 2015 The Authors http://creativecommons.org/licenses/by/4.0/ This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Birket, Matthew J.
Ribeiro, Marcelo C.
Kosmidis, Georgios
Ward, Dorien
Leitoguinho, Ana Rita
van de Pol, Vera
Dambrot, Cheryl
Devalla, Harsha D.
Davis, Richard P.
Mastroberardino, Pier G.
Atsma, Douwe E.
Passier, Robert
Mummery, Christine L.
Contractile Defect Caused by Mutation in MYBPC3 Revealed under Conditions Optimized for Human PSC-Cardiomyocyte Function
title Contractile Defect Caused by Mutation in MYBPC3 Revealed under Conditions Optimized for Human PSC-Cardiomyocyte Function
title_full Contractile Defect Caused by Mutation in MYBPC3 Revealed under Conditions Optimized for Human PSC-Cardiomyocyte Function
title_fullStr Contractile Defect Caused by Mutation in MYBPC3 Revealed under Conditions Optimized for Human PSC-Cardiomyocyte Function
title_full_unstemmed Contractile Defect Caused by Mutation in MYBPC3 Revealed under Conditions Optimized for Human PSC-Cardiomyocyte Function
title_short Contractile Defect Caused by Mutation in MYBPC3 Revealed under Conditions Optimized for Human PSC-Cardiomyocyte Function
title_sort contractile defect caused by mutation in mybpc3 revealed under conditions optimized for human psc-cardiomyocyte function
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4644234/
https://www.ncbi.nlm.nih.gov/pubmed/26489474
http://dx.doi.org/10.1016/j.celrep.2015.09.025
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