The regenerative capacity of the mammalian heart is very limited, so after damage, cardiomyocytes are lost and difficult to recover. Cardiac fibroblasts (cardiac fibroblast) respond to injury, activate and differentiate into myofibroblasts (myofibroblasts) also secrete collagen and other extracellular matrix to form scar tissue to repair the injury and prevent further damage to the heart. However, the scar tissue formed by myofibroblasts and extracellular matrix does not have the ability to contract, and the scar tissue cannot be eliminated, which will cause an increase in the burden on the heart for a long time, cause the remodeling of the heart structure, cause more cardiomyocytes to be lost, and ultimately lead to heart failure . Therefore, understand the activation and differentiation process of fibroblasts , prevent the formation of scar tissue, and have a very positive effect on the regeneration of heart tissue . Recently, the team of Prof. James F. Martin from Texas Heart Research Center has published a title of 27 Circulation Research 27 Cardio strong13 Span13span 27 strong signal from Yappan11span_strong18 's article,Reveals the important role of Yap in heart regeneration. It is reported that the first author of this article is a researcher at Texas Heart Research Center Liu Shijie , and Professor James F. Martin is the corresponding author.
Previous studies found that knocking out the Hippo signaling pathway in cardiomyocytes can promote heart regeneration after activating Yap. The team’s previous work found that Yap can not only activate the proliferation of cardiomyocytes, but also promote angiogenesis in the scar area and inhibit the formation of scar tissue in the heart. [2] . Since Hippo is only knocked out in cardiomyocytes, suggests that cardiomyocytes regulate the formation of blood vessels and scar tissue in the scar area through paracrine signals.
To this end, the authors examined the Yap downstream gene 5 in cardiomyocytes through ChIP-seq, nuclear-RNA-seq, and ATAC-seq, and found that Wnt signaling pathway genes are highly expressed in Yap Of myocardial cells are activated, including Wntless (Wls) . As a transmembrane protein, Wls mediates the processing and secretion of all Wnt signaling proteins6, 7. Based on this, speculates that Yap may be involved in the communication between cardiomyocytes and fibroblasts through the Wnt signal mediated by Wls.Promote heart regeneration. Knockout of
Wls will cause the Wnt signaling pathway in cardiomyocytes to fail to secrete. In order to study how Wls regulates heart regeneration in newborn mice, the author first analyzed cardiac single-cell sequencing data. found that non-canonical Wnt signaling proteins such as Wnt5a, Wnt5b, etc. are highly expressed in the heart. At the same time, it was found that Wnt signaling receptor molecules are growing The high expression in fibroblasts suggests that cardiomyocytes communicate with fibroblasts through the non-canonical Wnt signaling pathway. Wnt signaling molecules can bind to their receptors and phosphorylate on the receptor to activate downstream signal transduction . Further separating the cardiomyocytes of Wls knockout mice from non-cardiomyocytes, the authors found that the expression and phosphorylation of the classic Wnt signaling receptor LRP6 did not change significantly in non-cardiomyocytes, but not the expression of the classic Wnt signaling receptor ROR1 And the phosphorylation level decreased in the non-cardiomyocytes, indicating that the non-canonical Wnt signal derived from the cardiomyocytes received by the non-cardiomyocytes decreased after the Wls knockout of the cardiomyocytes.
The heart of newborn mice can regenerate after injury. In this study, a neonatal mouse model was used to quickly verify the function of Wls in the process of heart regeneration. First, CRISPR/Cas9 technology was used to knock down the Wls gene in neonatal mouse cardiomyocytes (Figure 1) , and the left anterior descending artery was ligated to induce cardiac infarct injury. After 4 weeks, the heart function was tested using echocardiography. The results showed that compared with the control group, the Wls knockdown mice had poorer heart function recovery, indicating that it has an important role in promoting heart regeneration in newborn mice.
Figure 1. Rapid knockout of Wls gene in cardiomyocytes by CRISPR/Cas9 technology _span13 _span
Constructed myocardial-specific Wls knockout mice,To further verify the important role of Wls in heart regeneration. Through RNA sequencing, found that after knockout of Wls in cardiomyocytes, many genes that are activated and differentiated from cardiac fibroblasts were significantly increased in non-cardiomyocytes. At the same time, histological analysis of the heart found that fibroblast proliferation and collagen The secretion of protein also increased, and the number of myofibroblasts also increased. It shows that cardiomyocytes can inhibit the activation and differentiation of cardiac fibroblasts through the non-canonical Wnt signaling pathway (Figure 2) .
Figure 2. Yap mediates the activation and differentiation of cardiac fibroblasts through the non-canonical Wnt signaling pathway in cardiomyocytes through Wls
_span0 p2p In other words, this study revealed for the first time the direct connection between the Hippo signaling pathway and the non-canonical Wnt signaling pathway, and demonstrated how they regulate the communication between cardiomyocytes and fibroblasts, thereby affecting the differentiation of fibroblasts after heart injury. It has important implications for the future treatment of cardiac fibrosis and scar formation caused by myocardial infarction . This article is from the BioArtMED WeChat public account. More cutting-edge information in the biological field is waiting for you to discover!
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