Large-scale microRNA functional high-throughput screening identifies miR-515-3p and miR-519e-3p as inducers of human cardiomyocyte proliferation

Harsha V Renikunta; Katina Lazarow; Yiqi Gong; Praphulla Chandra Shukla; Vanasa Nageswaran; Hector Giral; Adelheid Kratzer; Lennart Opitz; Felix B Engel; Arash Haghikia; Sarah Costantino; Francesco Paneni; Jens Peter von Kries; Katrin Streckfuss-Bömeke; Ulf Landmesser; Philipp Jakob

doi:10.1016/j.isci.2023.106593

Large-scale microRNA functional high-throughput screening identifies miR-515-3p and miR-519e-3p as inducers of human cardiomyocyte proliferation

iScience. 2023 Apr 8;26(5):106593. doi: 10.1016/j.isci.2023.106593. eCollection 2023 May 19.

Authors

Harsha V Renikunta^{1

2

3}, Katina Lazarow⁴, Yiqi Gong⁵, Praphulla Chandra Shukla^{1

2

6}, Vanasa Nageswaran^{1

2

3

7}, Hector Giral^{1

2}, Adelheid Kratzer^{1

2}, Lennart Opitz⁸, Felix B Engel⁹, Arash Haghikia^{1

2

3

10}, Sarah Costantino⁵, Francesco Paneni⁵, Jens Peter von Kries⁴, Katrin Streckfuss-Bömeke^{11

12

13}, Ulf Landmesser^{1

2

3

10}, Philipp Jakob^{1

2

3

5

10}

Affiliations

¹ Deutsches Herzzentrum der Charité, Department of Cardiology, Angiology and Intensive Care, Hindenburgdamm 30, 12203 Berlin, Germany.
² Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Charitéplatz 1, 10117 Berlin, Germany.
³ DZHK (German Center for Cardiovascular Research), partner site Berlin, Berlin, Germany.
⁴ Leibniz-Institute for Molecular Pharmacology (FMP), Campus Berlin-Buch, Robert-Rössle-Strasse 10, 13125 Berlin, Germany.
⁵ Center for Translational and Experimental Cardiology (CTEC), Department of Cardiology, University Hospital Zurich, University of Zurich, Wagistrasse 12, 8952 Schlieren, Switzerland.
⁶ School of Medical Science and Technology, Indian Institute of Technology, Kharagpur 721302, West Bengal, India.
⁷ Institute of Chemistry/Biochemistry, Thielallee 63, Freie Universität Berlin, 14195 Berlin, Germany.
⁸ Functional Genomics Center Zurich UZH/ETH, ETH Zurich and University of Zurich, 8057 Zurich, Switzerland.
⁹ Experimental Renal and Cardiovascular Research, Department of Nephropathology, Institute of Pathology, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Schwabachanlage 12 (TRC), 91054 Erlangen, Germany.
¹⁰ Berlin Institute of Health (BIH) at Charité - Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany.
¹¹ Clinic for Cardiology and Pneumology, University Medical Center Göttingen, Robert-Koch-Strasse 40, 37075 Göttingen, Germany.
¹² DZHK (German Center for Cardiovascular Research), partner site Göttingen, Robert-Koch-Strasse 42a, 37075 Göttingen, Germany.
¹³ Institute of Pharmacology and Toxicology, University of Würzburg, Versbacher Str. 9, 97078 Würzburg, Germany.

Abstract

Ischemic cardiomyopathy, driven by loss of cardiomyocytes and inadequate proliferative response, persists to be a major global health problem. Using a functional high-throughput screening, we assessed differential proliferative potential of 2019 miRNAs after transient hypoxia by transfecting both miR-inhibitor and miR-mimic libraries in human iPSC-CM. Whereas miR-inhibitors failed to enhance EdU uptake, overexpression of 28 miRNAs substantially induced proliferative activity in hiPSC-CM, with an overrepresentation of miRNAs belonging to the primate-specific C19MC-cluster. Two of these miRNAs, miR-515-3p and miR-519e-3p, increased markers of early and late mitosis, indicative of cell division, and substantially alter signaling pathways relevant for cardiomyocyte proliferation in hiPSC-CM.

Keywords: Cardiovascular medicine; Genetics; Molecular biology.