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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

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  • Media type: E-Article
  • Title: miR-128a Acts as a Regulator in Cardiac Development by Modulating Differentiation of Cardiac Progenitor Cell Populations
  • Contributor: 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.
  • Published: MDPI AG, 2020
  • Published in: International Journal of Molecular Sciences, 21 (2020) 3, Seite 1158
  • Language: English
  • DOI: 10.3390/ijms21031158
  • ISSN: 1422-0067
  • Origination:
  • Footnote:
  • 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.
  • Access State: Open Access