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

• Published in: Molecular therapy. Nucleic acids Vol. 29; pp. 481 - 497
• Main Authors: Wu, Yukang, Guo, Xudong, Han, Tong, Feng, Ke, Zhang, Peng, Xu, Yanxin, Yang, Yiwei, Xia, Yuchen, Chen, Yang, Xi, Jiajie, Yang, Huangtian, Wan, Xiaoping, Kang, Jiuhong
• Format: Journal Article
• Language: English
• Published: Elsevier Inc 13-09-2022; American Society of Gene & Cell Therapy; Elsevier
• Subjects: cardiac patch; cardiomyocyte maturation; Cmarr; DGC; Dtna; miR-540-3p; MT:Noncoding RNAs; myocardial infarction; Original; DGC; cardiac patch; miR-540-3p; Dtna; Cmarr; MT:Noncoding RNAs; myocardial infarction; cardiomyocyte maturation
• ISSN: 2162-2531; 2162-2531
• DOI: 10.1016/j.omtn.2022.07.022

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.
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Kang and colleagues described that lncRNA Cmarr competed with miR-540-3p and released its inhibition on Dtna expression, facilitating the DGC-YAP complex formation and promoting the maturation of mESC-CMs. They also showed that the Cmarr-engineered patch recovered the impaired function of MI heart and provided a functional lncRNA in cardiomyocyte maturation and MI treatment.