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Cell. 2018 Mar 22;173(1):104-116.e12. doi: 10.1016/j.cell.2018.02.014. Epub 2018 Mar 1.

Regulation of Cell Cycle to Stimulate Adult Cardiomyocyte Proliferation and Cardiac Regeneration.

Author information

1
Gladstone Institute of Cardiovascular Disease and Roddenberry Stem Cell Center, San Francisco, CA 94158, USA; Institute of Cardiovascular Sciences, University of Manchester, Manchester M13 9PT, UK; Faculty of Pharmacy, Zagazig University, Al Sharqia Governorate, Egypt; Tenaya Therapeutics, South San Francisco, CA 94080, USA.
2
Gladstone Institute of Cardiovascular Disease and Roddenberry Stem Cell Center, San Francisco, CA 94158, USA.
3
Department of Radiology, University of California San Francisco, San Francisco, CA 94158, USA.
4
Gladstone Institute of Cardiovascular Disease and Roddenberry Stem Cell Center, San Francisco, CA 94158, USA; Department of Pediatrics, University of California San Francisco, San Francisco, CA 94158, USA; Department of Biochemistry & Biophysics, University of California San Francisco, San Francisco, CA 94158, USA. Electronic address: deepak.srivastava@gladstone.ucsf.edu.

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

PMID:
29502971
PMCID:
PMC5973786
[Available on 2019-03-22]
DOI:
10.1016/j.cell.2018.02.014
[Indexed for MEDLINE]

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