Journal Article

Loss of microRNA-128 promotes cardiomyocyte proliferation and heart regeneration

Wang, Mingyang, Jiang, Lin, Medvedovic, Mario, Yu, Xi-Yong, Wang, Yigang, Yu, Hao, Stambrook, Peter J., Feng, Yuliang, Meng, Wei, Paul, Christian, Davidson, W. Sean, Sadayappan, Sakthivel, Huang, Wei, Liang, Jialiang, Wang, Cheng, Cai, Wenfeng, Chen, Jenny, Wang, Boyu

2018

Overview

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. During early postnatal development in mammals, cardiomyocytes exit the cell cycle, losing their regenerative capacity. Here the authors show that, following myocardial infarction, loss of microRNA-128 promotes cardiomyocyte proliferation and cardiac regeneration in adult mice partly via enhancing the expression of the chromatin modifier SUZ12.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13/51 / 13/95 / 14/63 / 38/77 / 45/91 / 631/136/2091 / 631/337/384/331 / 64/110 / 692/4019/592/2725 / 692/4019/592/2726 / Animals / Animals, Newborn / Cardiomyocytes / Cell Cycle / Cell Proliferation - genetics / Chromatin / Clonal deletion / Cyclin E / Cyclin E - metabolism / Cyclin-dependent kinase 2 / Cyclin-Dependent Kinase 2 - metabolism / Cyclin-dependent kinase inhibitor p27 / Cyclin-Dependent Kinase Inhibitor p27 - genetics / Cyclin-dependent kinases / Enzyme inhibitors / Fibrosis / Heart / Heart - physiology / Heart - physiopathology / Heart diseases / Humanities and Social Sciences / Mice / MicroRNAs / MicroRNAs - genetics / miRNA / multidisciplinary / Myocardial infarction / Myocardial Infarction - metabolism / Myocardial Infarction - pathology / Myocardial Infarction - physiopathology / Myocardium - metabolism / Myocardium - pathology / Myocytes, Cardiac - cytology / Neonates / Polycomb Repressive Complex 2 - genetics / Regeneration / Regeneration - genetics / Regulators / Ribonucleic acid / RNA / Science / Science (multidisciplinary)