Molecular mechanisms of cardiomyocyte differentiation and their therapeutic implications

1)IGFBP-4促进心肌细胞分化我们先前分离了IGFBP-4作为从基质细胞系OP-9分泌的心源性生长因子。在这项研究中，我们已经证明IGFBP-4通过抑制经典Wnt信号传导促进心肌细胞分化。我们还敲低了ES细胞和爪蟾胚胎中的IGFBP-4，以探讨内源性IGFBP-4对心肌细胞分化的作用。IGFBP-4的敲低导致ES细胞中心肌细胞分化的丧失和爪蟾胚胎中心脏形成的丧失，表明IGFBP-4对于体外和体内心肌发生都是必需的。2）心源性生长因子的下游信号传导在本研究中，我们探索了经典Wnt信号传导在ES细胞心肌细胞分化中的作用。在ES细胞分化的早期阶段，Wnt促进了心肌细胞的分化，而在晚期阶段，Wnt减弱了心肌细胞的分化，这表明经典的Wnt信号对心肌细胞分化的影响可能与其对心肌细胞分化的影响有关。 ...更多信息 双肌发生以发育阶段特异性方式是双相的。我们还建立了一种ES细胞系，该细胞系能够同时观察心肌细胞分化和Wnt信号传导的激活，这将是一个有用的工具，为进一步解剖的Wnt信号转导在心肌发生中的作用。3）α-激酶家族的蛋白激酶在体内心脏发育中的作用ALPK 3属于α-激酶家族的蛋白激酶，并促进心肌细胞分化时，在胚胎癌细胞系P19 CL 6过表达。为了探讨蛋白激酶α-激酶家族在体内心脏发育中的作用，制备ALPK 3敲除（KO）小鼠。ALKP 3 KO小鼠出生正常，未表现出明显的表型。为了测试α-激酶家族的不同成员之间是否存在遗传冗余，检查了心脏α-激酶（HAK）KO小鼠和ALPK 3/HAK双KO小鼠的表型。然而，这些小鼠也没有表现出明显的表型，表明这些激酶不是体内心脏发育所必需的。少

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