Molecular mechanisms of cardiomyocyte differentiation and their therapeutic implications

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1) Promotion of cardiomyocyte differentiation by IGFBP-4 We previously isolated IGFBP-4 as a cardiogenic growth factor secreted from a stromal cell line OP-9. In this study we have demonstrated that IGFBP-4 promotes cardiomyocyte differentiation by inhibiting canonical Wnt signaling. We also knocked down IGFBP-4 in ES cells and in Xenopus embryos to explore the role of endogenous IGFBP-4 on cardiomyocyte differentiation. Knockdown of IGFBP-4 resulted in a loss of cardiomyocyte differentiation in ES cells and loss of heart formation in Xenopus embryos, indicating that IGFBP-4 is essential for both in vitro and in vivo cardiomyogenesis.2) Downstream signaling of cardiogenic growth factors In this study we explored the role of canonical Wnt signaling in cardiomyocyte differentiation of ES cells. In the early phase of ES cell differentiation, Wnt promoted cardiomyocyte differentiation, whereas in the late phase Wnt attenuated it, suggesting that the effect of canonical Wnt signaling on car … More diomyogenesis is biphasic in a developmental stage-specific manner. We also established an ES cell line that enables simultaneous visualization of cardiomyocyte differentiation and activation of Wnt signaling, which will be a useful tool for further dissection of the role of Wnt signaling on cardiomyogenesis.3) Role of α-kinase family of protein kinases in heart development in vivo ALPK3 belongs to α-kinase family of protein kinases and promotes cardiomyocyte differentiation when overexpressed in embryonal carcinoma cell line P19CL6. To explore the role of α-kinase family of protein kinases in heart development in vivo, ALPK3 knockout (KO) mice were generated. ALKP3 KO mice were born normally and exhibited no obvious phenotype. To test whether there are genetic redundancies among different members of the α-kinase family, the phenotype of heart α-kinase (HAK) KO mice and ALPK3/HAK double KO mice were examined. However, these mice also exhibited no obvious phenotype, suggesting that these kinases are not essential for heart development in vivo. Less