不同阶段胚胎干细胞与原始胚胎干细胞的调控模块分析

Embryonic stem cells (ESCs) are immortal cells derived from the inner cell mass (ICM) or epiblast of the developing embryo. ESCs come (broadly) in two types, 'na?ve' ESCs that are thought to be close mimics of the ICM/epiblast and 'primed' ESCs that have a more differentiated phenotype. Both na?ve and primed ESCs from mouse and human have been derived, and they are often described as equivalent. Yet serious discrepancies exist between mouse and human na?ve and primed cells. Additionally neither cell type is a close match to the ICM or epiblast of the developing embryo. In this project we will computationally define the differences between the different cell types (na?ve, primed, ICM) and species (mouse, human). Using the extensive data available in mouse na?ve ESCs we will use a computational approach to generate a model of their gene regulation which we will then extrapolate to the other cell types, for which considerably less data exists. Using this computational approach we will predict novel regulators and using follow-up experiments we will validate these new regulators in the different cell types. This project will give insight into pluripotency and provide fundamental understanding of exactly what ESCs are, how they relate to the embryo and their properties. This will lead to a precise understanding of the state and capabilities of the distinct cell types. Increasing understanding of their potential use to derive useful cell types for cell therapy and translational research and so contribute new treatments for disease conditions.

得到具有更高发育潜能的人类胚胎干细胞在干细胞理论和应用中都有着极为重要的意义，本研究计划比较已知不同阶段的胚胎干细胞和原始胚胎细胞，从而深入理解多能性的调控机理。胚胎干细胞（ESCs）是从囊胚内细胞团（ICM）或上胚层中分离的干细胞株，包括原态（na?ve）和定态（primed）两种类型，其区别在于原态胚胎干细胞能与ICM细胞整合形成嵌合动物，而定态胚胎干细胞则不可以。尽管一直认为原态胚胎干细胞与ICM细胞在功能上是等同的，但其表达谱事实上具有非常明显的差异，小鼠和人中已经分离成功的几种胚胎干细胞没有一种细胞类型与内细胞团或上胚层细胞状态一致。本项目将严格定义这些胚胎干细胞之间的差别，以及它们与ICM细胞及上胚层细胞的关系，利用最优化的生物信息分析技术找出每种细胞类型的特异性调节模块。对胚胎干细胞不同状态的分子机制的深入了解，将有助于我们设计新的高效重编程技术，分离出新的多能干细胞类型。

胚胎干细胞（ESCs）是源自发育中胚胎的内细胞团（ICM）或外胚层的永生细胞。胚胎干细胞有两种类型，一是幼稚态（naïve）胚胎干细胞，被认为是近似与内细胞团（ICM）的模拟模型，而第二种待激活态（primed）胚胎干细胞具有更多的分化表型，类似于后期外胚层。我们有兴趣了解控制这些细胞类型的机制，特别是它们与成体体细胞的关系。我们还探索了将体细胞转化为多能干细胞的机制，作为细胞类型转换的模型。..在本项目资助中，我们探索了这些早期胚胎细胞类型与其他体细胞之间的关系。我们应用尖端计算算法来梳理研究这些关系，并使用这些技术来发现具有胚胎特异性的一系列基因。我们还发现了共同抑制因子NCoR / SMRT在细胞重编程过程中的作用，以及共同抑制因子的缺失如何促进体细胞重编程，最后我们研究了体细胞转化为胚胎干细胞类型时发生的染色质重塑。..总体而言，我们在理解细胞类型的概念方面取得了新的进展，尤其是对胚胎干细胞类型转换机制的研究，支撑和巩固了我们对干细胞重编程和干细胞分化的机理研究。

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