Abstract 1240: Developmental Stage-Specific Roles of Wnt/β-Catenin Signaling in Cardiomyogenesis
Although Wingless (Wg)/Wnt signaling has been implicated in heart development of multiple organisms, conflicting results have been reported regarding the role of canonical Wnt pathway in cardiac myogenesis. Wg/armadillo signaling promotes heart development in Drosophila, and Wnt/β-catenin signaling is required for cardiomyocyte differentiation of mouse embryonal carcinoma cells while activation of canonical Wnt signaling inhibits heart formation in avians and amphibians. Using in vitro system of mouse embryonic stem (ES) cell differentiation, we show here that Wnt/β-catenin signaling exhibits developmental stage-specific, biphasic, and antagonistic roles in cardiomyogenesis and hematopoiesis/vasculogenesis. Activation of the Wnt/β-catenin pathway in the early phase during embryoid body formation enhances ES cell differentiation into cardiomyocytes while suppressing the number of hematopoietic and vascular cell and the expression of hematopoietic and vascular genes. In contrast, Wnt/β-catenin signaling in the late phase attenuates cardiomyocyte differentiation while enhancing the expression of hematopoietic/vascular markers, which is mediated by the inhibition of bone morphogenetic protein signaling. Thus, Wnt/β-catenin signaling exhibits biphasic and antagonistic effects on cardiomyogenesis and hematopoiesis/vasculogenesis depending on the stage of development. Based on these observations, we established a novel protocol for ES cell differentiation into cardiomyocytes. Initial enhancement followed by inhibition of Wnt signaling enables highly efficient cardiomyocyte differentiation of ES cells. Our present work provides important clues both to the molecular dissection of signaling pathways that regulate heart, blood, and vessel formation during embryogenesis and to the development of novel therapeutic strategies for cardiac regenerative medicine.