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The L-type Ca(2+) Channels Blocker Nifedipine Represses Mesodermal Fate Determination in Murine Embryonic Stem Cells

Dihydropyridines (DHP), which nifedipine is a member of, preferentially block Ca(2+) channels of different cell types. Moreover, influx of Ca(2+) through L-type Ca(2+) channels (LTCCs) activates Ca(2+) signaling pathways, which in turn contribute to numerous cellular processes. Although LTCCs are ex...

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Autores principales: Nguemo, Filomain, Fleischmann, Bernd K., Gupta, Manoj K., Šarić, Tomo, Malan, Daniela, Liang, Huamin, Pfannkuche, Kurt, Bloch, Wilhelm, Schunkert, Heribert, Hescheler, Jürgen, Reppel, Michael
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3539992/
https://www.ncbi.nlm.nih.gov/pubmed/23320083
http://dx.doi.org/10.1371/journal.pone.0053407
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author Nguemo, Filomain
Fleischmann, Bernd K.
Gupta, Manoj K.
Šarić, Tomo
Malan, Daniela
Liang, Huamin
Pfannkuche, Kurt
Bloch, Wilhelm
Schunkert, Heribert
Hescheler, Jürgen
Reppel, Michael
author_facet Nguemo, Filomain
Fleischmann, Bernd K.
Gupta, Manoj K.
Šarić, Tomo
Malan, Daniela
Liang, Huamin
Pfannkuche, Kurt
Bloch, Wilhelm
Schunkert, Heribert
Hescheler, Jürgen
Reppel, Michael
author_sort Nguemo, Filomain
collection PubMed
description Dihydropyridines (DHP), which nifedipine is a member of, preferentially block Ca(2+) channels of different cell types. Moreover, influx of Ca(2+) through L-type Ca(2+) channels (LTCCs) activates Ca(2+) signaling pathways, which in turn contribute to numerous cellular processes. Although LTCCs are expressed in undifferentiated cells, very little is known about its contributions to the transcriptional regulation of mesodermal and cardiac genes. This study aimed to examine the contribution of LTCCs and the effect of nifedipine on the commitment of pluripotent stem cells toward the cardiac lineage in vitro. The murine embryonic stem (ES, cell line D3) and induced pluripotent stem (iPS, cell clone 09) cells were differentiated into enhanced green fluorescence protein (EGFP) expressing spontaneously beating cardiomyocytes (CMs). Early treatment of differentiating cells with 10 µM nifedipine led to a significant inhibition of the cardiac mesoderm formation and cardiac lineage commitment as revealed by gene regulation analysis. This was accompanied by the inhibition of spontaneously occurring Ca(2+) transient and reduction of LTCCs current density (I (CaL)) of differentiated CMs. In addition, nifedipine treatment instigated a pronounced delay of the spontaneous beating embryoid body (EB) and led to a poor surface localization of L-type Ca(2+) channel α(1C) (Ca(V)1.2) subunits. Contrary late incubation of pluripotent stem cells with nifedipine was without any impact on the differentiation process and did not affect the derived CMs function. Our data indicate that nifedipine blocks the determined path of pluripotent stem cells to cardiomyogenesis by inhibition of mesodermal commitment at early stages of differentiation, thus the proper upkeep Ca(2+) concentration and pathways are essentially required for cardiac gene expression, differentiation and function.
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spelling pubmed-35399922013-01-14 The L-type Ca(2+) Channels Blocker Nifedipine Represses Mesodermal Fate Determination in Murine Embryonic Stem Cells Nguemo, Filomain Fleischmann, Bernd K. Gupta, Manoj K. Šarić, Tomo Malan, Daniela Liang, Huamin Pfannkuche, Kurt Bloch, Wilhelm Schunkert, Heribert Hescheler, Jürgen Reppel, Michael PLoS One Research Article Dihydropyridines (DHP), which nifedipine is a member of, preferentially block Ca(2+) channels of different cell types. Moreover, influx of Ca(2+) through L-type Ca(2+) channels (LTCCs) activates Ca(2+) signaling pathways, which in turn contribute to numerous cellular processes. Although LTCCs are expressed in undifferentiated cells, very little is known about its contributions to the transcriptional regulation of mesodermal and cardiac genes. This study aimed to examine the contribution of LTCCs and the effect of nifedipine on the commitment of pluripotent stem cells toward the cardiac lineage in vitro. The murine embryonic stem (ES, cell line D3) and induced pluripotent stem (iPS, cell clone 09) cells were differentiated into enhanced green fluorescence protein (EGFP) expressing spontaneously beating cardiomyocytes (CMs). Early treatment of differentiating cells with 10 µM nifedipine led to a significant inhibition of the cardiac mesoderm formation and cardiac lineage commitment as revealed by gene regulation analysis. This was accompanied by the inhibition of spontaneously occurring Ca(2+) transient and reduction of LTCCs current density (I (CaL)) of differentiated CMs. In addition, nifedipine treatment instigated a pronounced delay of the spontaneous beating embryoid body (EB) and led to a poor surface localization of L-type Ca(2+) channel α(1C) (Ca(V)1.2) subunits. Contrary late incubation of pluripotent stem cells with nifedipine was without any impact on the differentiation process and did not affect the derived CMs function. Our data indicate that nifedipine blocks the determined path of pluripotent stem cells to cardiomyogenesis by inhibition of mesodermal commitment at early stages of differentiation, thus the proper upkeep Ca(2+) concentration and pathways are essentially required for cardiac gene expression, differentiation and function. Public Library of Science 2013-01-08 /pmc/articles/PMC3539992/ /pubmed/23320083 http://dx.doi.org/10.1371/journal.pone.0053407 Text en © 2013 Nguemo et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Nguemo, Filomain
Fleischmann, Bernd K.
Gupta, Manoj K.
Šarić, Tomo
Malan, Daniela
Liang, Huamin
Pfannkuche, Kurt
Bloch, Wilhelm
Schunkert, Heribert
Hescheler, Jürgen
Reppel, Michael
The L-type Ca(2+) Channels Blocker Nifedipine Represses Mesodermal Fate Determination in Murine Embryonic Stem Cells
title The L-type Ca(2+) Channels Blocker Nifedipine Represses Mesodermal Fate Determination in Murine Embryonic Stem Cells
title_full The L-type Ca(2+) Channels Blocker Nifedipine Represses Mesodermal Fate Determination in Murine Embryonic Stem Cells
title_fullStr The L-type Ca(2+) Channels Blocker Nifedipine Represses Mesodermal Fate Determination in Murine Embryonic Stem Cells
title_full_unstemmed The L-type Ca(2+) Channels Blocker Nifedipine Represses Mesodermal Fate Determination in Murine Embryonic Stem Cells
title_short The L-type Ca(2+) Channels Blocker Nifedipine Represses Mesodermal Fate Determination in Murine Embryonic Stem Cells
title_sort l-type ca(2+) channels blocker nifedipine represses mesodermal fate determination in murine embryonic stem cells
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3539992/
https://www.ncbi.nlm.nih.gov/pubmed/23320083
http://dx.doi.org/10.1371/journal.pone.0053407
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