Regulation of Human Embryonic Stem Cells by Wnts

WNT信号通路调节胚胎细胞的增殖、分化、极性和行为 在成人干细胞、癌症和其他疾病状态下的发育。因此，WNTS是合理的 在人类胚胎干细胞(HESCs)的正常生物学中发挥重要作用的候选人和 改变体外培养的人胚胎干细胞的增殖和分化。至少两条Wnt信号通路 存在于脊椎动物中，Wnt/Li-catenin途径通过明确定义的 途径，以及一个或多个可以拮抗Wnt/B-catenin途径的“非规范”途径。在……里面 多种干细胞Wnt/Li-catenin途径参与控制自我更新、增殖、 和差异化。相反，hESCs中非正则通路的存在或功能并没有 已经上报了。这个项目的总体目标是测试不同的Wnt信号通路 都在功能上参与人胚胎干细胞的体外增殖和分化，以阐明不同的 信号机制，并利用这些洞察力来指导hESC的体外分化。具体的 目标是： 目的1.询问hESC中不同的Wnt信号通路 目的2.miRNAs对人类胚胎干细胞中Wnt通路的调控 目的3.人类胚胎干细胞对WNT-3a和WNT-5a梯度的反应 总的来说，拟议的研究将进一步深入了解监管的基础机制 Wnt信号转导hESCs，尤其是Wnts在hESC增殖、分化中的作用 和能动性。这些发现可以被用来在体外操纵人类胚胎干细胞，最终目标是 生成hESC分化方案，可对人类疾病产生治疗影响。

Wnt signaling pathways regulate cell proliferation, differentiation, polarity, and behavior in embryonic development, in adult stem cells, and in cancers and other disease states. Wnts are therefore reasonable candidates for playing essential roles in the normal biology of human embryonic stem cells (hESCs) and for altering the proliferation and differentiation of hESCs cultured in vitro. At least two Wnt signaling pathways exist in vertebrates, the Wnt/li-catenin pathway that controls gene expression through a well-defined pathway, and one or more "non-canonical" pathways that can antagonize the Wnt/B-catenin pathway. In various stem cells the Wnt/li-catenin pathway has been implicated in controlling self-renewal, proliferation, and differentiation. In contrast, the existence or functions of the non-canonical pathways in hESCs have not been reported. The overall goal of this project is to test the hypothesis that distinct Wnt signaling pathways are functionally involved in the in vitro proliferation and differentiation of hESCs, to elucidate the different mechanisms of signaling, and to leverage these insights to direct hESC differentiation in vitro. The specific aimsare: Aim 1. Interrogating distinct Wnt signaling pathways in hESC Aim 2. Regulation of Wnt pathways in hESCs by miRNAs Aim 3. Responses of hESCs to gradients of Wnt-3a and Wnt-5a ^ Collectively, the proposed studies will lend further insight into the mechanisms underlying the regulation of hESCs by Wnt signaling, particularly with regards to the role of Wnts in hESC proliferation, differentiation and motility. These findings can be exploited to manipulate hESCs in vitro with the eventual goal of generating protocols for hESC differentiation that can have therapeutic impact on human disease.