Cmarr/miR-540-3p axis promotes cardiomyocyte maturation transition by orchestrating Dtna expression

Yukang Wu; Xudong Guo; Tong Han; Ke Feng; Peng Zhang; Yanxin Xu; Yiwei Yang; Yuchen Xia; Yang Chen; Jiajie Xi; Huangtian Yang; Xiaoping Wan; Jiuhong Kang

doi:10.1016/j.omtn.2022.07.022

Cmarr/miR-540-3p axis promotes cardiomyocyte maturation transition by orchestrating Dtna expression

Mol Ther Nucleic Acids. 2022 Jul 31:29:481-497. doi: 10.1016/j.omtn.2022.07.022. eCollection 2022 Sep 13.

Authors

Yukang Wu¹, Xudong Guo^{1

2}, Tong Han³, Ke Feng¹, Peng Zhang⁴, Yanxin Xu¹, Yiwei Yang¹, Yuchen Xia¹, Yang Chen¹, Jiajie Xi¹, Huangtian Yang⁴, Xiaoping Wan³, Jiuhong Kang¹

Affiliations

¹ Clinical and Translational Research Center of Shanghai First Maternity and Infant Hospital, Shanghai Key Laboratory of Maternal Fetal Medicine, Shanghai Key Laboratory of Signaling and Disease Research, Frontier Science Center for Stem Cell Research, National Stem Cell Translational Resource Center, School of Life Sciences and Technology, Tongji University, Shanghai 200092, China.
² Institute for Advanced Study, Tongji University, Shanghai 200092, China.
³ Department of Gynecology, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Tongji University, Shanghai 200040, China.
⁴ CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China.

Abstract

The immature phenotype of embryonic stem cell-derived cardiomyocytes (ESC-CMs) limits their application. However, the molecular mechanisms of cardiomyocyte maturation remain largely unexplored. This study found that overexpression of long noncoding RNA (lncRNA)-Cmarr, which was highly expressed in cardiomyocytes, promoted the maturation change and physiological maturation of mouse ESC-CMs (mESC-CMs). Moreover, transplantation of cardiac patch overexpressing Cmarr exhibited better retention of mESC-CMs, reduced infarct area by enhancing vascular density in the host heart, and improved cardiac function in mice after myocardial infarction. Mechanism studies identified that Cmarr acted as a competitive endogenous RNA to impede the repression of miR-540-3p on Dtna expression and promoted the binding of the dystrophin-glycoprotein complex (DGC) and yes-associated protein (YAP), which in turn reduced the proportion of nuclear YAP and the expression of YAP target genes. Therefore, this study revealed the function and mechanism of Cmarr in promoting cardiomyocyte maturation and provided a lncRNA that can be used as a functional factor in the construction of cardiac patches for the treatment of myocardial infarction.

Keywords: Cmarr; DGC; Dtna; MT:Noncoding RNAs; cardiac patch; cardiomyocyte maturation; miR-540-3p; myocardial infarction.