Loss of microRNA-128 promotes cardiomyocyte proliferation and heart regeneration

Wei Huang, Yuliang Feng, Jialiang Liang, Hao Yu, Cheng Wang, Boyu Wang, Mingyang Wang, Lin Jiang, Wei Meng, Wenfeng Cai, Mario Medvedovic, Jenny Chen, Christian Paul, W. Sean Davidson, Sakthivel Sadayappan, Peter J. Stambrook, Xi-Yong Yu () and Yigang Wang ()
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Wei Huang: Guangzhou Medical University
Yuliang Feng: Guangzhou Medical University
Jialiang Liang: University of Cincinnati College of Medicine
Hao Yu: University of Cincinnati College of Medicine
Cheng Wang: Radboud University
Boyu Wang: Samaritan Medical Center
Mingyang Wang: University of Cincinnati
Lin Jiang: University of Cincinnati College of Medicine
Wei Meng: The Third Affiliated Hospital of Sun Yat-sen University
Wenfeng Cai: University of Cincinnati College of Medicine
Mario Medvedovic: University of Cincinnati College of Medicine
Jenny Chen: University of Cincinnati College of Medicine
Christian Paul: University of Cincinnati College of Medicine
W. Sean Davidson: University of Cincinnati College of Medicine
Sakthivel Sadayappan: University of Cincinnati College of Medicine
Peter J. Stambrook: University of Cincinnati College of Medicine
Xi-Yong Yu: Guangzhou Medical University
Yigang Wang: University of Cincinnati College of Medicine

Nature Communications, 2018, vol. 9, issue 1, 1-16

Abstract: Abstract The goal of replenishing the cardiomyocyte (CM) population using regenerative therapies following myocardial infarction (MI) is hampered by the limited regeneration capacity of adult CMs, partially due to their withdrawal from the cell cycle. Here, we show that microRNA-128 (miR-128) is upregulated in CMs during the postnatal switch from proliferation to terminal differentiation. In neonatal mice, cardiac-specific overexpression of miR-128 impairs CM proliferation and cardiac function, while miR-128 deletion extends proliferation of postnatal CMs by enhancing expression of the chromatin modifier SUZ12, which suppresses p27 (cyclin-dependent kinase inhibitor) expression and activates the positive cell cycle regulators Cyclin E and CDK2. Furthermore, deletion of miR-128 promotes cell cycle re-entry of adult CMs, thereby reducing the levels of fibrosis, and attenuating cardiac dysfunction in response to MI. These results suggest that miR-128 serves as a critical regulator of endogenous CM proliferation, and might be a novel therapeutic target for heart repair.

Date: 2018
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DOI: 10.1038/s41467-018-03019-z

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