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Bone morphogenetic protein 4 promotes the differentiation of Tbx18-positive epicardial progenitor cells to pacemaker-like cells
Clarifying the mechanisms via which pacemaker- like cells are generated is critical for identifying novel targets for arrhythmia-associated disorders and constructing pacemakers with the ability to adapt to physiological requirements. T-box 18 (Tbx18)(+) epicardial progenitor cells (EPCs) have the p...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
D.A. Spandidos
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6425233/ https://www.ncbi.nlm.nih.gov/pubmed/30906456 http://dx.doi.org/10.3892/etm.2019.7243 |
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author | Wu, Ling Du, Jianlin Jing, Xiaodong Yan, Yuling Deng, Songbai Hao, Zhengtao She, Qiang |
author_facet | Wu, Ling Du, Jianlin Jing, Xiaodong Yan, Yuling Deng, Songbai Hao, Zhengtao She, Qiang |
author_sort | Wu, Ling |
collection | PubMed |
description | Clarifying the mechanisms via which pacemaker- like cells are generated is critical for identifying novel targets for arrhythmia-associated disorders and constructing pacemakers with the ability to adapt to physiological requirements. T-box 18 (Tbx18)(+) epicardial progenitor cells (EPCs) have the potential to differentiate into pacemaker cells. Although bone morphogenetic protein 4 (Bmp4) is likely to contribute, its role and regulatory mechanisms in the differentiation of Tbx18(+) EPCs into pacemaker-like cells have remained to be fully elucidated. In the present study, the association between Bmp4, GATA binding protein 4 (Gata4) and hyperpolarization- activated cyclic nucleotide gated potassium channel 4 (Hcn4) to regulate NK2 homeobox 5 (Nkx2.5), which is known to be required for the differentiation of Tbx18(+) EPCs into pacemaker-like cells, was assessed. Tbx18(+) EPCs were isolated from Tbx18:Cre/Rosa26R(enhanced yellow fluorescence protein (EYFP)) murine embryos at embryonic day 11.5 and divided into the following four treatment groups: Control, Bmp4, Bmp4+LDN193189 (a Bmp inhibitor) and LDN193189. In vitro Bmp4 promoted the expression of Hcn4 in Tbx18(+) EPCs via lineage tracing of Tbx18:Cre/Rosa26R(EYFP) mice, which was likely due to upregulation of Gata4 expression. Gata4 knockdown experiments were then performed using the following five treatment groups: Control, control small interfering RNA (siRNA), Bmp4, Bmp4+siRNA targeting Gata4 (siGata4) and siGata4 group. Knockdown of Gata4 caused a downregulation of Hcn4 and an upregulation of Nkx2.5, but had no effect on Bmp4 expression. In conclusion, it was indicated that in Tbx18(+) EPCs, the expression of Nkx2.5 was regulated by Bmp4 via Gata4. Taken together, these results provide important information on regulatory networks of pacemaker cell differentiation and may serve as a basis for further studies. |
format | Online Article Text |
id | pubmed-6425233 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | D.A. Spandidos |
record_format | MEDLINE/PubMed |
spelling | pubmed-64252332019-03-22 Bone morphogenetic protein 4 promotes the differentiation of Tbx18-positive epicardial progenitor cells to pacemaker-like cells Wu, Ling Du, Jianlin Jing, Xiaodong Yan, Yuling Deng, Songbai Hao, Zhengtao She, Qiang Exp Ther Med Articles Clarifying the mechanisms via which pacemaker- like cells are generated is critical for identifying novel targets for arrhythmia-associated disorders and constructing pacemakers with the ability to adapt to physiological requirements. T-box 18 (Tbx18)(+) epicardial progenitor cells (EPCs) have the potential to differentiate into pacemaker cells. Although bone morphogenetic protein 4 (Bmp4) is likely to contribute, its role and regulatory mechanisms in the differentiation of Tbx18(+) EPCs into pacemaker-like cells have remained to be fully elucidated. In the present study, the association between Bmp4, GATA binding protein 4 (Gata4) and hyperpolarization- activated cyclic nucleotide gated potassium channel 4 (Hcn4) to regulate NK2 homeobox 5 (Nkx2.5), which is known to be required for the differentiation of Tbx18(+) EPCs into pacemaker-like cells, was assessed. Tbx18(+) EPCs were isolated from Tbx18:Cre/Rosa26R(enhanced yellow fluorescence protein (EYFP)) murine embryos at embryonic day 11.5 and divided into the following four treatment groups: Control, Bmp4, Bmp4+LDN193189 (a Bmp inhibitor) and LDN193189. In vitro Bmp4 promoted the expression of Hcn4 in Tbx18(+) EPCs via lineage tracing of Tbx18:Cre/Rosa26R(EYFP) mice, which was likely due to upregulation of Gata4 expression. Gata4 knockdown experiments were then performed using the following five treatment groups: Control, control small interfering RNA (siRNA), Bmp4, Bmp4+siRNA targeting Gata4 (siGata4) and siGata4 group. Knockdown of Gata4 caused a downregulation of Hcn4 and an upregulation of Nkx2.5, but had no effect on Bmp4 expression. In conclusion, it was indicated that in Tbx18(+) EPCs, the expression of Nkx2.5 was regulated by Bmp4 via Gata4. Taken together, these results provide important information on regulatory networks of pacemaker cell differentiation and may serve as a basis for further studies. D.A. Spandidos 2019-04 2019-02-04 /pmc/articles/PMC6425233/ /pubmed/30906456 http://dx.doi.org/10.3892/etm.2019.7243 Text en Copyright: © Wu et al. This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License (https://creativecommons.org/licenses/by-nc-nd/4.0/) , which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. |
spellingShingle | Articles Wu, Ling Du, Jianlin Jing, Xiaodong Yan, Yuling Deng, Songbai Hao, Zhengtao She, Qiang Bone morphogenetic protein 4 promotes the differentiation of Tbx18-positive epicardial progenitor cells to pacemaker-like cells |
title | Bone morphogenetic protein 4 promotes the differentiation of Tbx18-positive epicardial progenitor cells to pacemaker-like cells |
title_full | Bone morphogenetic protein 4 promotes the differentiation of Tbx18-positive epicardial progenitor cells to pacemaker-like cells |
title_fullStr | Bone morphogenetic protein 4 promotes the differentiation of Tbx18-positive epicardial progenitor cells to pacemaker-like cells |
title_full_unstemmed | Bone morphogenetic protein 4 promotes the differentiation of Tbx18-positive epicardial progenitor cells to pacemaker-like cells |
title_short | Bone morphogenetic protein 4 promotes the differentiation of Tbx18-positive epicardial progenitor cells to pacemaker-like cells |
title_sort | bone morphogenetic protein 4 promotes the differentiation of tbx18-positive epicardial progenitor cells to pacemaker-like cells |
topic | Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6425233/ https://www.ncbi.nlm.nih.gov/pubmed/30906456 http://dx.doi.org/10.3892/etm.2019.7243 |
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