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Open AccessArticle

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

1
Department of Cardiovascular Surgery, German Heart Center Munich at the Technische Universität München, 80636 Munich, Germany
2
Institute for Translational Cardiac Surgery (INSURE), Cardiovascular Surgery, 80636 Munich, Germany
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German Center for Cardiovascular Research (DZHK)—Partner Site Munich Heart Alliance, Biedersteiner Strasse 29, 80802 München, Germany
4
Institute for Cardiogenetics, University of Lübeck, 23562 Lübeck, Germany
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Heart Center Lübeck, University of Lübeck, 23562 Lübeck, Germany
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German Center for Cardiovascular Research (DZHK)—Partner Site Hamburg/Lübeck/Kiel, 20246 Hamburg, Germany
7
Department of Cardiology, German Heart Center Munich at the Technische Universität München, 80636 Munich, Germany
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Medical Department 1, Cardiology, Klinikum rechts der Isar, Technische Universität, 81675 Munich, Germany
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Department of Experimental and Clinical Medicine, Stem Cell Laboratory, Research Center of Advanced Biochemistry and Molecular Biology, University “Magna Graecia” of Catanzaro, Viale Europa, 88100 Catanzaro, Italy
10
Institute of Experimental and Clinical Pharmacology and Toxicology, Faculty of Medicine, University of Freiburg, Albertstrasse 25, 79104 Freiburg, Germany
11
Institute for Cardiovascular Physiology, Goethe University, Theodor-Stern-Kai 7, 60596 Frankfurt am Main, Germany
12
German Center for Cardiovascular Research (DZHK)—Partner Site RheinMain, 61231 Bad Nauheim, Germany
13
BIOSS Centre for Biological Signaling Studies, University of Freiburg, Schänzlestrasse 1, 79104 Freiburg, Germany
14
Department of Medicine III, Cardiology, Angiology, Pneumology, University Hospital Heidelberg, 69120 Heidelberg, Germany
15
German Center for Cardiovascular Research (DZHK)—Partner Site Heidelberg/Mannheim, 69120 Heidelberg, Germany
*
Authors to whom correspondence should be addressed.
Markus Krane and Stefanie A. Doppler contributed equally to this manuscript.
Int. J. Mol. Sci. 2020, 21(3), 1158; https://doi.org/10.3390/ijms21031158
Received: 10 January 2020 / Revised: 4 February 2020 / Accepted: 6 February 2020 / Published: 10 February 2020
(This article belongs to the Section Molecular Biology)
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. View Full-Text
Keywords: microRNA; miR-128; cardiac development; cardiac progenitor cells; Nkx2.5 cardiac enhancer microRNA; miR-128; cardiac development; cardiac progenitor cells; Nkx2.5 cardiac enhancer
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Hoelscher, S.C.; Stich, T.; Diehm, A.; Lahm, H.; Dreßen, M.; Zhang, Z.; Neb, I.; Aherrahrou, Z.; Erdmann, J.; Schunkert, H.; Santamaria, G.; Cuda, G.; Gilsbach, R.; Hein, L.; Lange, R.; Hassel, D.; Krane, M.; Doppler, S.A. miR-128a Acts as a Regulator in Cardiac Development by Modulating Differentiation of Cardiac Progenitor Cell Populations. Int. J. Mol. Sci. 2020, 21, 1158.

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