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

Area of Science:

• Cardiovascular Biology
• Stem Cell Biology
• Molecular Medicine

Background:

• Embryonic stem cell-derived cardiomyocytes (ESC-CMs) possess an immature phenotype, limiting their therapeutic applications.
• The molecular mechanisms governing cardiomyocyte maturation are not well understood.

Purpose of the Study:

• To investigate the role of long noncoding RNA (lncRNA)-Cmarr in promoting cardiomyocyte maturation.
• To explore the therapeutic potential of Cmarr in a myocardial infarction model.

Main Methods:

• Overexpression of lncRNA-Cmarr in mouse ESC-CMs (mESC-CMs).
• Transplantation of cardiac patches engineered with Cmarr-overexpressing mESC-CMs into mice post-myocardial infarction.
• Mechanistic studies involving competitive endogenous RNA (ceRNA) activity, microRNA (miR-540-3p) targeting, and the dystrophin-glycoprotein complex (DGC)-YAP pathway.

Main Results:

• Overexpression of Cmarr promoted both the phenotypic and physiological maturation of mESC-CMs.
• Cmarr-overexpressing cardiac patches enhanced mESC-CM retention, reduced infarct size, increased vascular density, and improved cardiac function in mice.
• Cmarr functions as a ceRNA, inhibiting miR-540-3p's repression of Dtna and modulating the DGC-YAP interaction, thereby reducing nuclear YAP and its target gene expression.

Conclusions:

• lncRNA-Cmarr plays a crucial role in promoting cardiomyocyte maturation.
• Cmarr holds promise as a functional factor for cardiac patch construction in treating myocardial infarction.