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Dual Modulation of the Mitochondrial Permeability Transition Pore and Redox Signaling Synergistically Promotes Cardiomyocyte Differentiation From Pluripotent Stem Cells

BACKGROUND: Cardiomyocytes that differentiate from pluripotent stem cells (PSCs) provide a crucial cellular resource for cardiac regeneration. The mechanisms of mitochondrial metabolic and redox regulation for efficient cardiomyocyte differentiation are, however, still poorly understood. Here, we sh...

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Autores principales: Cho, Sung Woo, Park, Jin‐Sung, Heo, Hye Jin, Park, Sang‐Wook, Song, Sukhyun, Kim, Injune, Han, Yong‐Mahn, Yamashita, Jun K., Youm, Jae Boum, Han, Jin, Koh, Gou Young
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Blackwell Publishing Ltd 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4187507/
https://www.ncbi.nlm.nih.gov/pubmed/24627421
http://dx.doi.org/10.1161/JAHA.113.000693
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author Cho, Sung Woo
Park, Jin‐Sung
Heo, Hye Jin
Park, Sang‐Wook
Song, Sukhyun
Kim, Injune
Han, Yong‐Mahn
Yamashita, Jun K.
Youm, Jae Boum
Han, Jin
Koh, Gou Young
author_facet Cho, Sung Woo
Park, Jin‐Sung
Heo, Hye Jin
Park, Sang‐Wook
Song, Sukhyun
Kim, Injune
Han, Yong‐Mahn
Yamashita, Jun K.
Youm, Jae Boum
Han, Jin
Koh, Gou Young
author_sort Cho, Sung Woo
collection PubMed
description BACKGROUND: Cardiomyocytes that differentiate from pluripotent stem cells (PSCs) provide a crucial cellular resource for cardiac regeneration. The mechanisms of mitochondrial metabolic and redox regulation for efficient cardiomyocyte differentiation are, however, still poorly understood. Here, we show that inhibition of the mitochondrial permeability transition pore (mPTP) by Cyclosporin A (CsA) promotes cardiomyocyte differentiation from PSCs. METHODS AND RESULTS: We induced cardiomyocyte differentiation from mouse and human PSCs and examined the effect of CsA on the differentiation process. The cardiomyogenic effect of CsA mainly resulted from mPTP inhibition rather than from calcineurin inhibition. The mPTP inhibitor NIM811, which does not have an inhibitory effect on calcineurin, promoted cardiomyocyte differentiation as much as CsA did, but calcineurin inhibitor FK506 only slightly increased cardiomyocyte differentiation. CsA‐treated cells showed an increase in mitochondrial calcium, mitochondrial membrane potential, oxygen consumption rate, ATP level, and expression of genes related to mitochondrial function. Furthermore, inhibition of mitochondrial oxidative metabolism reduced the cardiomyogenic effect of CsA while antioxidant treatment augmented the cardiomyogenic effect of CsA. CONCLUSIONS: Our data show that mPTP inhibition by CsA alters mitochondrial oxidative metabolism and redox signaling, which leads to differentiation of functional cardiomyocytes from PSCs.
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spelling pubmed-41875072014-11-03 Dual Modulation of the Mitochondrial Permeability Transition Pore and Redox Signaling Synergistically Promotes Cardiomyocyte Differentiation From Pluripotent Stem Cells Cho, Sung Woo Park, Jin‐Sung Heo, Hye Jin Park, Sang‐Wook Song, Sukhyun Kim, Injune Han, Yong‐Mahn Yamashita, Jun K. Youm, Jae Boum Han, Jin Koh, Gou Young J Am Heart Assoc Original Research BACKGROUND: Cardiomyocytes that differentiate from pluripotent stem cells (PSCs) provide a crucial cellular resource for cardiac regeneration. The mechanisms of mitochondrial metabolic and redox regulation for efficient cardiomyocyte differentiation are, however, still poorly understood. Here, we show that inhibition of the mitochondrial permeability transition pore (mPTP) by Cyclosporin A (CsA) promotes cardiomyocyte differentiation from PSCs. METHODS AND RESULTS: We induced cardiomyocyte differentiation from mouse and human PSCs and examined the effect of CsA on the differentiation process. The cardiomyogenic effect of CsA mainly resulted from mPTP inhibition rather than from calcineurin inhibition. The mPTP inhibitor NIM811, which does not have an inhibitory effect on calcineurin, promoted cardiomyocyte differentiation as much as CsA did, but calcineurin inhibitor FK506 only slightly increased cardiomyocyte differentiation. CsA‐treated cells showed an increase in mitochondrial calcium, mitochondrial membrane potential, oxygen consumption rate, ATP level, and expression of genes related to mitochondrial function. Furthermore, inhibition of mitochondrial oxidative metabolism reduced the cardiomyogenic effect of CsA while antioxidant treatment augmented the cardiomyogenic effect of CsA. CONCLUSIONS: Our data show that mPTP inhibition by CsA alters mitochondrial oxidative metabolism and redox signaling, which leads to differentiation of functional cardiomyocytes from PSCs. Blackwell Publishing Ltd 2014-04-25 /pmc/articles/PMC4187507/ /pubmed/24627421 http://dx.doi.org/10.1161/JAHA.113.000693 Text en © 2014 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell. This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial (http://creativecommons.org/licenses/by-nc/3.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.
spellingShingle Original Research
Cho, Sung Woo
Park, Jin‐Sung
Heo, Hye Jin
Park, Sang‐Wook
Song, Sukhyun
Kim, Injune
Han, Yong‐Mahn
Yamashita, Jun K.
Youm, Jae Boum
Han, Jin
Koh, Gou Young
Dual Modulation of the Mitochondrial Permeability Transition Pore and Redox Signaling Synergistically Promotes Cardiomyocyte Differentiation From Pluripotent Stem Cells
title Dual Modulation of the Mitochondrial Permeability Transition Pore and Redox Signaling Synergistically Promotes Cardiomyocyte Differentiation From Pluripotent Stem Cells
title_full Dual Modulation of the Mitochondrial Permeability Transition Pore and Redox Signaling Synergistically Promotes Cardiomyocyte Differentiation From Pluripotent Stem Cells
title_fullStr Dual Modulation of the Mitochondrial Permeability Transition Pore and Redox Signaling Synergistically Promotes Cardiomyocyte Differentiation From Pluripotent Stem Cells
title_full_unstemmed Dual Modulation of the Mitochondrial Permeability Transition Pore and Redox Signaling Synergistically Promotes Cardiomyocyte Differentiation From Pluripotent Stem Cells
title_short Dual Modulation of the Mitochondrial Permeability Transition Pore and Redox Signaling Synergistically Promotes Cardiomyocyte Differentiation From Pluripotent Stem Cells
title_sort dual modulation of the mitochondrial permeability transition pore and redox signaling synergistically promotes cardiomyocyte differentiation from pluripotent stem cells
topic Original Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4187507/
https://www.ncbi.nlm.nih.gov/pubmed/24627421
http://dx.doi.org/10.1161/JAHA.113.000693
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