Multi-omic analysis reveals VEGFR2, PI3K, and JNK mediate the small molecule induction of human iPSC-derived cardiomyocyte proliferation
Laura A. Woo,
Kaitlyn L. Wintruba,
Bethany Wissmann,
Svyatoslav Tkachenko,
Ewa Kubicka,
Emily Farber,
Ola Engkvist,
Ian Barrett,
Kenneth L. Granberg,
Alleyn T. Plowright,
Matthew J. Wolf,
David L. Brautigan,
Stefan Bekiranov,
Qing-Dong Wang,
Jeffrey J. Saucerman
Affiliations
Laura A. Woo
Department of Biomedical Engineering and Robert M. Berne Cardiovascular Research Center, University of Virginia, Charlottesville, VA 22903, USA
Kaitlyn L. Wintruba
Department of Biomedical Engineering and Robert M. Berne Cardiovascular Research Center, University of Virginia, Charlottesville, VA 22903, USA
Bethany Wissmann
Department of Biomedical Engineering and Robert M. Berne Cardiovascular Research Center, University of Virginia, Charlottesville, VA 22903, USA
Svyatoslav Tkachenko
Quantitative Health Sciences, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH 44196, USA
Ewa Kubicka
Center for Cell Signaling, Department of Microbiology, Immunology & Cancer Biology, University of Virginia, Charlottesville, VA 22903, USA
Emily Farber
Department of Biochemistry and Molecular Genetics, University of Virginia, Charlottesville, VA 22903, USA
Ola Engkvist
Molecular AI, Discovery Sciences, R&D, AstraZeneca, 43150 Gothenburg, MöIndal, Sweden
Ian Barrett
Data Sciences & Quantitative Biology, Discovery Sciences, R&D, AstraZeneca, Cambridge CB40WG, England
Kenneth L. Granberg
Medicinal Chemistry, Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, 43150 Gothenburg, MöIndal, Sweden
Alleyn T. Plowright
Medicinal Chemistry, Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, 43150 Gothenburg, MöIndal, Sweden
Matthew J. Wolf
Department of Medicine and Robert M. Berne Cardiovascular Research Center, University of Virginia, Charlottesville, VA 22903, USA
David L. Brautigan
Center for Cell Signaling, Department of Microbiology, Immunology & Cancer Biology, University of Virginia, Charlottesville, VA 22903, USA
Stefan Bekiranov
Department of Biochemistry and Molecular Genetics, University of Virginia, Charlottesville, VA 22903, USA
Qing-Dong Wang
Bioscience Cardiovascular, Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, 43150 Gothenburg, MöIndal, Sweden
Jeffrey J. Saucerman
Department of Biomedical Engineering and Robert M. Berne Cardiovascular Research Center, University of Virginia, Charlottesville, VA 22903, USA; Corresponding author
Summary: Mammalian hearts lose their regenerative potential shortly after birth. Stimulating the proliferation of preexisting cardiomyocytes is a potential therapeutic strategy for cardiac damage. In a previous study, we identified 30 compounds that induced the bona-fide proliferation of human iPSC-derived cardiomyocytes (hiPSC-CM). Here, we selected five active compounds with diverse targets, including ALK5 and CB1R, and performed multi-omic analyses to identify common mechanisms mediating the cell cycle progression of hiPSC-CM. Transcriptome profiling revealed the top enriched pathways for all compounds including cell cycle, DNA repair, and kinesin pathways. Functional proteomic arrays found that the compounds collectively activated multiple receptor tyrosine kinases including ErbB2, IGF1R, and VEGFR2. Network analysis integrating common transcriptomic and proteomic signatures predicted that MAPK/PI3K pathways mediated compound responses. Furthermore, VEGFR2 negatively regulated endoreplication, enabling the completion of cell division. Thus, in this study, we applied high-content imaging and molecular profiling to establish mechanisms linking pro-proliferative agents to mechanisms of cardiomyocyte cell cycling.
