【原】mTOR 支持长期自我更新，同时抑制人类胚胎干细胞的中胚层和内胚层活动

mTOR supports long-term self-renewal and suppresses mesoderm and endoderm activities of human embryonic stem cells

---

|核心内容：

尽管最近发现的转录调控电路包括 SOX2、 NANOG 和 OCT-4，但是控制人类胚胎干细胞(hESCs)多能性的细胞内信号网络仍然很大程度上是未确定的。

Fig. 1. Inhibition or depletion of mTOR disrupts pluripotency of hESCs.

在这里，我们证明了丝氨酸/苏氨酸蛋白激酶哺乳动物雷帕霉素靶蛋白(mTOR)在调节 hESC 长期未分化生长中的重要作用。

图2. mTOR抑制可诱导内胚层和中胚层活动，并抑制细胞增殖

mTOR的抑制会损伤多能性，阻止细胞增殖，增强中胚层和内胚层活性。

在分子水平上，mTOR 整合来自外部多能性支持因子的信号，并抑制发育和生长抑制性基因亚群的转录活动，正如全基因组芯片分析所揭示的那样。

Fig. 3. mTOR integrates extrinsic pluripotency-supporting signals

mTOR 抑制发育基因是维持胚胎干细胞多能性的必要条件。

Fig. 4. mTOR represses expression of growth inhibitory and developmental genes in hESCs.

这些结果揭示了一种新的信号机制，通过 mTOR 控制 hESCs 的命运决定。我们的发现可能有助于组织修复和再生的有效策略。

图5. mTOR通过促进细胞增殖和抑制分化来支持hESC的长期自我更新的一种模型。  mTOR对bFGF、MEF-CM和KSR等外在因素有反应，整合并传递多能支持信号。激活mTOR抑制Wnt信号通路，结合未知机制（虚线；问号）抑制MIXL1、Brachyury(T基因)、EBF2和PITX2在hESCs中的转录活性。抑制发育基因是OCT-4/SOX2/NANOG网络稳定性所必需的。mTOR还抑制生长抑制分子，包括Cyclin G2和PDCD4，从而促进细胞增殖。

原文摘要：

Despite the recent identification of the transcriptional regulatory circuitry involving SOX2, NANOG, and OCT-4, the intracellular signaling networks that control pluripotency of human embryonic stem cells (hESCs) remain largely undefined. 

Here, we demonstrate an essential role for the serine/threonine protein kinase mammalian target of rapamycin (mTOR) in regulating hESC long-term undifferentiated growth. 

Inhibition of mTOR impairs pluripotency, prevents cell proliferation, and enhances mesoderm and endoderm activities in hESCs.

At the molecular level, mTOR integrates signals from extrinsic pluripotency-supporting factors and represses the transcriptional activities of a subset of developmental and growthinhibitory genes, as revealed by genome-wide microarray analyses. Repression of the developmental genes by mTOR is necessary for the maintenance of hESC pluripotency. These results uncover a novel signaling mechanism by which mTOR controls fate decisions in hESCs. Our findings may contribute to effective strategies for tissue repair and regeneration.

---

参考文献：https:///10.1073/pnas.0901854106

-------------------------------------------------------------------------