Abstract
Human diseases are often caused by loss of somatic cells that are incapable of re-entering the cell cycle for regenerative repair. Here, we report a combination of cell-cycle regulators that induce stable cytokinesis in adult post-mitotic cells. We screened cell-cycle regulators expressed in proliferating fetal cardiomyocytes and found that overexpression of cyclin-dependent kinase 1 (CDK1), CDK4, cyclin B1, and cyclin D1 efficiently induced cell division in post-mitotic mouse, rat, and human cardiomyocytes. Overexpression of the cell-cycle regulators was self-limiting through proteasome-mediated degradation of the protein products. In vivo lineage tracing revealed that 15%-20% of adult cardiomyocytes expressing the four factors underwent stable cell division, with significant improvement in cardiac function after acute or subacute myocardial infarction. Chemical inhibition of Tgf-β and Wee1 made CDK1 and cyclin B dispensable. These findings reveal a discrete combination of genes that can efficiently unlock the proliferative potential in cells that have terminally exited the cell cycle.
Keywords:
CDK; cardiomyocyte; cell cycle; cell division; cyclin; cytokinesis; heart; heart failure; proliferation; regeneration.
Copyright © 2018 Elsevier Inc. All rights reserved.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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CDC2 Protein Kinase / genetics
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CDC2 Protein Kinase / metabolism
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Cell Cycle Proteins / antagonists & inhibitors
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Cell Cycle Proteins / metabolism
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Cell Proliferation
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Cyclin B1 / genetics
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Cyclin B1 / metabolism
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Cyclin D1 / genetics
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Cyclin D1 / metabolism
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Cyclin-Dependent Kinase 4 / genetics
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Cyclin-Dependent Kinase 4 / metabolism
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Cytokinesis
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Heart / physiology*
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Humans
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Induced Pluripotent Stem Cells / cytology
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Induced Pluripotent Stem Cells / metabolism
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Mice
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Mice, Inbred C57BL
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Mice, Transgenic
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Myocardial Infarction / metabolism
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Myocardial Infarction / pathology
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Myocardial Infarction / veterinary
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Myocytes, Cardiac / cytology
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Myocytes, Cardiac / metabolism*
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Myosin Heavy Chains / genetics
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Nuclear Proteins / antagonists & inhibitors
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Nuclear Proteins / metabolism
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Protein-Tyrosine Kinases / antagonists & inhibitors
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Protein-Tyrosine Kinases / metabolism
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Rats
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Regeneration
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Transforming Growth Factor beta / antagonists & inhibitors
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Transforming Growth Factor beta / metabolism
Substances
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Cell Cycle Proteins
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Cyclin B1
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Myh6 protein, mouse
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Nuclear Proteins
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Transforming Growth Factor beta
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Cyclin D1
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Protein-Tyrosine Kinases
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Wee1 protein, mouse
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CDC2 Protein Kinase
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Cyclin-Dependent Kinase 4
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Myosin Heavy Chains