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miR-128a Acts as a Regulator in Cardiac Development by Modulating Differentiation of Cardiac Progenitor Cell Populations

MicroRNAs (miRs) appear to be major, yet poorly understood players in regulatory networks guiding cardiogenesis. We sought to identify miRs with unknown functions during cardiogenesis analyzing the miR-profile of multipotent Nkx2.5 enhancer cardiac progenitor cells (NkxCE-CPCs). Besides well-known c...

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Autores principales: Hoelscher, Sarah C., Stich, Theresia, Diehm, Anne, Lahm, Harald, Dreßen, Martina, Zhang, Zhong, Neb, Irina, Aherrahrou, Zouhair, Erdmann, Jeanette, Schunkert, Heribert, Santamaria, Gianluca, Cuda, Giovanni, Gilsbach, Ralf, Hein, Lutz, Lange, Rüdiger, Hassel, David, Krane, Markus, Doppler, Stefanie A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7038042/
https://www.ncbi.nlm.nih.gov/pubmed/32050579
http://dx.doi.org/10.3390/ijms21031158
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author Hoelscher, Sarah C.
Stich, Theresia
Diehm, Anne
Lahm, Harald
Dreßen, Martina
Zhang, Zhong
Neb, Irina
Aherrahrou, Zouhair
Erdmann, Jeanette
Schunkert, Heribert
Santamaria, Gianluca
Cuda, Giovanni
Gilsbach, Ralf
Hein, Lutz
Lange, Rüdiger
Hassel, David
Krane, Markus
Doppler, Stefanie A.
author_facet Hoelscher, Sarah C.
Stich, Theresia
Diehm, Anne
Lahm, Harald
Dreßen, Martina
Zhang, Zhong
Neb, Irina
Aherrahrou, Zouhair
Erdmann, Jeanette
Schunkert, Heribert
Santamaria, Gianluca
Cuda, Giovanni
Gilsbach, Ralf
Hein, Lutz
Lange, Rüdiger
Hassel, David
Krane, Markus
Doppler, Stefanie A.
author_sort Hoelscher, Sarah C.
collection PubMed
description MicroRNAs (miRs) appear to be major, yet poorly understood players in regulatory networks guiding cardiogenesis. We sought to identify miRs with unknown functions during cardiogenesis analyzing the miR-profile of multipotent Nkx2.5 enhancer cardiac progenitor cells (NkxCE-CPCs). Besides well-known candidates such as miR-1, we found about 40 miRs that were highly enriched in NkxCE-CPCs, four of which were chosen for further analysis. Knockdown in zebrafish revealed that only miR-128a affected cardiac development and function robustly. For a detailed analysis, loss-of-function and gain-of-function experiments were performed during in vitro differentiations of transgenic murine pluripotent stem cells. MiR-128a knockdown (1) increased Isl1, Sfrp5, and Hcn4 (cardiac transcription factors) but reduced Irx4 at the onset of cardiogenesis, (2) upregulated Isl1-positive CPCs, whereas NkxCE-positive CPCs were downregulated, and (3) increased the expression of the ventricular cardiomyocyte marker Myl2 accompanied by a reduced beating frequency of early cardiomyocytes. Overexpression of miR-128a (4) diminished the expression of Isl1, Sfrp5, Nkx2.5, and Mef2c, but increased Irx4, (5) enhanced NkxCE-positive CPCs, and (6) favored nodal-like cardiomyocytes (Tnnt2(+), Myh6(+), Shox2(+)) accompanied by increased beating frequencies. In summary, we demonstrated that miR-128a plays a so-far unknown role in early heart development by affecting the timing of CPC differentiation into various cardiomyocyte subtypes.
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spelling pubmed-70380422020-03-10 miR-128a Acts as a Regulator in Cardiac Development by Modulating Differentiation of Cardiac Progenitor Cell Populations Hoelscher, Sarah C. Stich, Theresia Diehm, Anne Lahm, Harald Dreßen, Martina Zhang, Zhong Neb, Irina Aherrahrou, Zouhair Erdmann, Jeanette Schunkert, Heribert Santamaria, Gianluca Cuda, Giovanni Gilsbach, Ralf Hein, Lutz Lange, Rüdiger Hassel, David Krane, Markus Doppler, Stefanie A. Int J Mol Sci Article MicroRNAs (miRs) appear to be major, yet poorly understood players in regulatory networks guiding cardiogenesis. We sought to identify miRs with unknown functions during cardiogenesis analyzing the miR-profile of multipotent Nkx2.5 enhancer cardiac progenitor cells (NkxCE-CPCs). Besides well-known candidates such as miR-1, we found about 40 miRs that were highly enriched in NkxCE-CPCs, four of which were chosen for further analysis. Knockdown in zebrafish revealed that only miR-128a affected cardiac development and function robustly. For a detailed analysis, loss-of-function and gain-of-function experiments were performed during in vitro differentiations of transgenic murine pluripotent stem cells. MiR-128a knockdown (1) increased Isl1, Sfrp5, and Hcn4 (cardiac transcription factors) but reduced Irx4 at the onset of cardiogenesis, (2) upregulated Isl1-positive CPCs, whereas NkxCE-positive CPCs were downregulated, and (3) increased the expression of the ventricular cardiomyocyte marker Myl2 accompanied by a reduced beating frequency of early cardiomyocytes. Overexpression of miR-128a (4) diminished the expression of Isl1, Sfrp5, Nkx2.5, and Mef2c, but increased Irx4, (5) enhanced NkxCE-positive CPCs, and (6) favored nodal-like cardiomyocytes (Tnnt2(+), Myh6(+), Shox2(+)) accompanied by increased beating frequencies. In summary, we demonstrated that miR-128a plays a so-far unknown role in early heart development by affecting the timing of CPC differentiation into various cardiomyocyte subtypes. MDPI 2020-02-10 /pmc/articles/PMC7038042/ /pubmed/32050579 http://dx.doi.org/10.3390/ijms21031158 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Hoelscher, Sarah C.
Stich, Theresia
Diehm, Anne
Lahm, Harald
Dreßen, Martina
Zhang, Zhong
Neb, Irina
Aherrahrou, Zouhair
Erdmann, Jeanette
Schunkert, Heribert
Santamaria, Gianluca
Cuda, Giovanni
Gilsbach, Ralf
Hein, Lutz
Lange, Rüdiger
Hassel, David
Krane, Markus
Doppler, Stefanie A.
miR-128a Acts as a Regulator in Cardiac Development by Modulating Differentiation of Cardiac Progenitor Cell Populations
title miR-128a Acts as a Regulator in Cardiac Development by Modulating Differentiation of Cardiac Progenitor Cell Populations
title_full miR-128a Acts as a Regulator in Cardiac Development by Modulating Differentiation of Cardiac Progenitor Cell Populations
title_fullStr miR-128a Acts as a Regulator in Cardiac Development by Modulating Differentiation of Cardiac Progenitor Cell Populations
title_full_unstemmed miR-128a Acts as a Regulator in Cardiac Development by Modulating Differentiation of Cardiac Progenitor Cell Populations
title_short miR-128a Acts as a Regulator in Cardiac Development by Modulating Differentiation of Cardiac Progenitor Cell Populations
title_sort mir-128a acts as a regulator in cardiac development by modulating differentiation of cardiac progenitor cell populations
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7038042/
https://www.ncbi.nlm.nih.gov/pubmed/32050579
http://dx.doi.org/10.3390/ijms21031158
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