Abstract 308: Wls Inhibits Fibrosis Through Wnt Secretion From the Cardiomyocytes During Heart Regeneration

Abstract

Because cardiomyocytes lose their capacity for self-renewal shortly after birth, the heart cannot regenerate muscle lost due to injury or heart failure. Instead, dead myocardium is replaced with a fibrotic scar. Recent studies have demonstrated that blocking the Hippo pathway specifically in cardiomyocytes promotes heart functional recovery after injury, not only by stimulating cardiomyocyte proliferation, but also by preventing fibrosis. The mechanism through which YAP activates the cell cycle is widely studied; however, the mechanism through which it inhibits fibrosis is unknown. Here, we identified Wntless ( Wls ) to be a downstream target of YAP in regenerating cardiomyocytes; Wls plays a role in regulating the secretion of Wnt ligands, which influences interstitial cells through paracrine effects. By using Adeno-Associated Virus 9 (AAV9) to deliver guide RNAs (gRNAs) that target the Wls locus exclusively in cardiomyocytes that express the Cas9 protein, we generated a cardiomyocyte-specific Wls knock out mouse (Wls-Cas9 CKO). After myocardial infarction at the neonatal stage (regenerative stage), cardiomyocyte deletion of Wls detrimental the heart regeneration as showed decreased heart function and increased fibrosis in Wls-Cas9 CKO mice. Mechanistically, by performing nuclear RNA-Seq technology, we revealed that non-canonical Wnt ligands are enriched in cardiomyocytes suggest cardiomyocytes influence fibroblasts through non-canonical signaling during heart regeneration. We will further use the single-cell sequencing technology to investigate the cell to cell communication during heart regeneration.