胚胎干细胞向中内胚层分化的早期命运决定机制

胚胎干细胞是一类具有自我复制和无限扩增能力的多向潜能细胞。其在临床上有广泛的应用前景。然而如何提高干细胞替代疗法的安全性和高效性是目前临床应用的难题。因此，理解干细胞早期分化命运决定机制是掌握其分化功能的前提条件。我们的预实验提示，关键中内胚层基因的特定增强子是接收分化信号，并整合表观遗传和信号调控的首要元件。我们假设中内胚层分化信号首先通过“开关”因子传递到这些特定增强子上。被活化开放的增强子进而激活蓄势待发的启动子，最终启动中内胚层基因的表达。本研究将以Eomes、T和Gsc等关键中内胚层基因作为研究模型，致力于阐明胚胎干细胞向中内胚层分化的早期命运决定机制，寻找早期分化的“开关”蛋白，探索开关信号通路和表观遗传网络，以及二者相互作用的机制。该研究有望揭示多能性和分化调控之间的命运决定机制，从原理上掌握如何正确“打开”与“关闭”胚胎干细胞的分化功能，势必推进干细胞在临床上的应用。

Embryonic stem cells (ESCs) are pluripotent stem cells as they can self-renew and differentiate into cells of all three germ layers, shown by teratoma and embryoid body (EB) formation. Since ESCs have the ability to differentiate into clinically relevant cell types, there is tremendous interest in using these cells both in basic biological research and in transplantation medicine. However, how to improve the safety and efficiency of stem cell replacement therapy is still a challenge. Therefore, understanding the early fate-determination of ESCs is a prerequisite for mastering ESCs’ differentiation function. .. Our preliminary experiments suggest that specific enhancers of key mesendoderm genes are the primary elements receiving differentiation signals, as well as integrating epigenetic regulation and signal transduction. We hypothesize that mesendoderm differentiation signals are first transmitted to these specific enhancers through "switch" factors, which then activate poised promoters to initiate expression of mesendoderm genes. In this study, key mesendoderm genes such as Eomes, T and Gsc are used as research models. We will explore the mechanism of ESCs’ early fate-determination towards mesendoderm, clarify the interaction of epigenetic regulation and signal transduction networks. This work will help us understand how to correctly “turn on” and “turn off” the differentiation function of ESCs, which will finally promote the clinical application of stem cells.