Regulation of Human Embryonic Stem Cell Self-Renewal

自我更新是干细胞的两个定义属性之一，了解 管理自我更新是干细胞生物学中最重要的问题之一。与老鼠不同的是，几乎没有 已知人类胚胎干细胞(HESCs)的自我更新计划，需要未定义或 极其复杂的培养条件。我们最近发现了一种简单的方法来培养小鼠、恒河猴和 人类ES细胞使用低浓度的丁酸盐，在hESCs中，它激活一种替代的和 分子上不同的转录程序。我们假设这种不同的转录模式导致 丁酸盐是丁酸盐自我更新计划的因果联系，而不是反映。本项目 建议使用丁酸盐和我们实验室的其他最新进展来探索分子基础 的自我更新。在具体目标1中，我们将区分丁酸盐是否选择用于自我更新的hESCs 或者在特定的目标2中重新编程hESCs，我们将检查丁酸盐对hESCs的影响是否可逆。 在特定目标3中，我们将确定hESC自身所必需或足够的丁酸反应基因 更新。在特定的目标4中，我们将检查特定的基因组基因座，这些基因座似乎受 丁酸盐。

Self renewal is one of the two defining properties of a stem cell, and understanding the mechanisms that govern self renewal is among the most important problems in stem cell biology. Unlike mouse, very little is known about the self renewal program of human embryonic stem cells (hESCs), which require undefined or extremely complex culture conditions. We have recently found a simple way to culture mouse, rhesus and human ES cells using a low concentration of butyrate which, in hESCs, activates an alternative and molecularly distinct transcriptional program. We hypothesize that the distinct transcriptional profile induced by butyrate is causally linked to, rather than reflective of, the butyrate self renewal program. This Project proposes to use butyrate and other recent developments from our lab to probe the molecular underpinnings of hESC self renewal. In Specific Aim 1 we will distinguish whether butyrate selects for self renewing hESCs or reprograms hESCs In Specific Aim 2 we will examine whether butyrate's effects on hESCs are reversible. In Specific Aim 3 we will identify butyrate responsive genes that are necessary or sufficient for hESC self renewal. In Specific Aim 4 we will examine specific genomic loci that appear to be coordinately regulated by butyrate.