Wnt/β-Catenin signaling acts at multiple developmental stages to promote mammalian cardiogenesis

Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, California, United States
Cell cycle (Georgetown, Tex.) (Impact Factor: 4.57). 01/2009; 7(24):3815-8. DOI: 10.4161/cc.7.24.7189
Source: PubMed


Despite decades of progress in cardiovascular biology, heart disease remains the leading cause of death in the developed world. Recently, cell-based therapy has emerged as a promising avenue for future therapeutics. However, the molecular signals that regulate cardiac progenitor cells are not well-understood. Wnt/beta-catenin signaling is essential for expansion and differentiation of cardiac progenitors in mouse embryos and in the embryonic stem cell system. Studies from our laboratory and others highlight the pivotal roles of Wnt/beta-catenin signaling in the multiple steps of cardiogenesis and provide insights into understanding the complex regulation of cardiac progenitors. Here we discuss the required roles of Wnt/beta-catenin signaling at the different stages of heart development.

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    • "Wnt/beta-catenin signaling has previously been established to play a biphasic role in cardiac differentiation of EBs [44], [45], [46]. Specification of early cardiac progenitor cells is promoted, while later differentiation of progenitor cells into cardiomyocytes is repressed by Wnt/beta-catenin signaling [44], [45], [46]. Since we showed above that endogenous CS could negatively regulate the Wnt/beta-catenin pathway in EBs, we hypothesized that CS has a similar biphasic role in cardiac differentiation through its ability to regulate the Wnt/beta-catenin pathway. "
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    ABSTRACT: The glycosaminoglycan chondroitin sulfate is a critical component of proteoglycans on the cell surface and in the extracellular matrix. As such, chondroitin sulfate side chains and the sulfation balance of chondroitin play important roles in the control of signaling pathways, and have a functional importance in human disease. In contrast, very little is known about the roles of chondroitin sulfate molecules and sulfation patterns during mammalian development and cell lineage specification. Here, we report a novel biphasic role of chondroitin sulfate in the specification of the cardiac cell lineage during embryonic stem cell differentiation through modulation of Wnt/beta-catenin signaling. Lineage marker analysis demonstrates that enzymatic elimination of endogenous chondroitin sulfates leads to defects specifically in cardiac differentiation. This is accompanied by a reduction in the number of beating cardiac foci. Mechanistically, we show that endogenous chondroitin sulfate controls cardiac differentiation in a temporal biphasic manner through inhibition of the Wnt/beta-catenin pathway, a known regulatory pathway for the cardiac lineage. Treatment with a specific exogenous chondroitin sulfate, CS-E, could mimic these biphasic effects on cardiac differentiation and Wnt/beta-catenin signaling. These results establish chondroitin sulfate and its sulfation balance as important regulators of cardiac cell lineage decisions through control of the Wnt/beta-catenin pathway. Our work suggests that targeting the chondroitin biosynthesis and sulfation machinery is a novel promising avenue in regenerative strategies after heart injury.
    PLoS ONE 03/2014; 9(3):e92381. DOI:10.1371/journal.pone.0092381 · 3.23 Impact Factor
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    • "The cardiovascular system requires precisely regulated canonical Wnt/β-catenin (Wnt) signaling in order to develop properly, as Wnt signaling has been shown to both promote and restrict cardiomyocyte (CM) formation during distinct phases of development (Kwon et al., 2008; Tzahor, 2007). Understanding how Wnt signaling directs CM development is necessary for the generation of therapies capable of healing injured or malformed human hearts. "
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    Developmental Biology 05/2013; 380(2). DOI:10.1016/j.ydbio.2013.05.016 · 3.55 Impact Factor
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    • "The second or “epigenetic” relates to heritable changes in gene function that occur independently of alterations in primary DNA sequence. The best-characterized epigenetic modifications are DNA methylation and histone modifications, both of which function in Wnt signaling, a critical pathway in early cardiomyogenesis [24, 44, 45, 47, 93], neurogenesis [50, 94–96], and placentation [48]. Vertebrate DNA methylation is in general restricted to cytosine (C) nucleotides in the sequence CG, known as CpG islands. "
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