Basic Study
Copyright ©The Author(s) 2019. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Stem Cells. Dec 26, 2019; 11(12): 1130-1141
Published online Dec 26, 2019. doi: 10.4252/wjsc.v11.i12.1130
MiR-301a promotes embryonic stem cell differentiation to cardiomyocytes
Li-Xiao Zhen, Yu-Ying Gu, Qian Zhao, Hui-Fang Zhu, Jin-Hui Lv, Shu-Jun Li, Zhen Xu, Li Li, Zuo-Ren Yu
Li-Xiao Zhen, Yu-Ying Gu, Qian Zhao, Hui-Fang Zhu, Jin-Hui Lv, Shu-Jun Li, Li Li, Zuo-Ren Yu, Key Laboratory of Arrhythmias of the Ministry of Education of China, Tongji University School of Medicine, Shanghai 200120, China
Li-Xiao Zhen, Yu-Ying Gu, Qian Zhao, Jin-Hui Lv, Shu-Jun Li, Li Li, Zuo-Ren Yu, Research Center for Translational Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China
Zhen Xu, Department of Microbiology and Immunology, Wenzhou Medical College, Wenzhou 325000, Zhejiang Province, China
Author contributions: Zhen LX, Zhao Q, Zhu HF, Lv JH, Li SJ, and Xu Z performed the experiments; Li L and Zhao Q performed the data analysis; Yu ZR and Gu YY designed the project and wrote the paper.
Supported by the National Natural Science Foundation of China, No. 81800243; the Science and Technology Commission of Shanghai Municipality, No. 18411965900; the Fundamental Research Funds for the Central Universities, No. 22120180125.
Institutional animal care and use committee statement: Animal studies were approved by the Institutional Animal Care and Use Committee of the Tongji University School of Medicine (No. TJLAC-016-028).
Conflict-of-interest statement: There are no conflicts of interest associated with this manuscript.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See:
Corresponding author: Zuo-Ren Yu, PhD, Professor, Research Center for Translational Medicine, Shanghai East Hospital, Tongji University School of Medicine, 150 Jimo Road, Shanghai 200120, China.
Telephone: +86-21-61569842 Fax: +86-21-61569842
Received: June 17, 2019
Peer-review started: June 19, 2019
First decision: July 31, 2019
Revised: September 23, 2019
Accepted: October 14, 2019
Article in press: October 14, 2019
Published online: December 26, 2019
Research background

After myocardial infarction (MI) in adults, the regenerative ability of the differentiated cardiomyocytes is very limited due to the “terminated” cell proliferative ability and the lack of cardiac stem cells. Tissue repair after pathological injury in the heart, including that after MI, is still a major clinical challenge. Two novel strategies have been suggested to restore the lost cardiomyocytes caused by MI. One is to apply cardiomyocytes differentiated from stem cells or derived from cardiospheres, and the other is to induce cell cycle reentry in cardiomyocytes.

Research motivation

Stem cells and stem cell-derived cardiomyocytes have been demonstrated to be a promising source for cell transplantation-based treatment of injured hearts. Modification of approaches to induce cardiac cell differentiation from stem cells with high efficiency will be crucial to improve the therapeutic effect.

Research objectives

To explore the function of miR-301a in regulating cardiomyocyte differentiation of mouse embryonic stem cells, and provide experimental evidence for applying miR-301a to the cardiomyocyte differentiation induction from stem cells.

Research methods

The hanging drop technique was applied to form embryoid bodies from mouse embryonic stem cells with or without overexpression of miR-301a. Cardiac markers including GATA-4, TBX5, and MEF2C, and α-actinin were used to determine cardiomyocyte differentiation from mouse embryonic stem cells.

Research results

MiR-301a was identified as a miRNA highly enriched in the heart from late embryonic to neonatal mice. Overexpression of miR-301a in mouse embryonic stem cells significantly induced the expression of cardiac transcription factors, thereby promoting cardiomyocyte differentiation and beating cardiomyocyte clone formation. PTEN was demonstrated to be a target gene of miR-301a in cardiomyocytes. PTEN-regulated AKT-mTOR-Stat3 signaling was involved in regulation of miR-301a-induced cardiomyocyte differentiation.

Research conclusions

MiR-301a is capable of promoting embryonic stem cell differentiation to cardiomyocytes. As such, miR-301a has potential as a novel target gene to induce cardiomyocyte differentiation.

Research perspectives

These findings will be beneficial in development of an approach with high efficiency to induce stem cell differentiation to cardiomyocytes, and strengthen the potential of cell therapeutics to treat heart failure caused by myocardial infarction.