mTOR supports long-term self-renewal andsuppresses mesoderm and endoderm activitiesof human embryonic stem cells
|核心內(nèi)容：
盡管最近發(fā)現(xiàn)的轉(zhuǎn)錄調(diào)控電路包括 SOX2、 NANOG 和 OCT-4，但是控制人類胚胎干細(xì)胞(hESCs)多能性的細(xì)胞內(nèi)信號網(wǎng)絡(luò)仍然很大程度上是未確定的。
Fig. 1. Inhibition or depletion of mTOR disrupts pluripotency of hESCs.
在這里，我們證明了絲氨酸/蘇氨酸蛋白激酶哺乳動物雷帕霉素靶蛋白(mTOR)在調(diào)節(jié) hESC 長期未分化生長中的重要作用。
圖2. mTOR抑制可誘導(dǎo)內(nèi)胚層和中胚層活動，并抑制細(xì)胞增殖
mTOR的抑制會損傷多能性，阻止細(xì)胞增殖，增強(qiáng)中胚層和內(nèi)胚層活性。
在分子水平上，mTOR 整合來自外部多能性支持因子的信號，并抑制發(fā)育和生長抑制性基因亞群的轉(zhuǎn)錄活動，正如全基因組芯片分析所揭示的那樣。
Fig. 3. mTOR integrates extrinsic pluripotency-supporting signals
mTOR 抑制發(fā)育基因是維持胚胎干細(xì)胞多能性的必要條件。
Fig. 4. mTOR represses expression of growth inhibitory and developmental genes in hESCs.
這些結(jié)果揭示了一種新的信號機(jī)制，通過 mTOR 控制 hESCs 的命運(yùn)決定。我們的發(fā)現(xiàn)可能有助于組織修復(fù)和再生的有效策略。
圖5. mTOR通過促進(jìn)細(xì)胞增殖和抑制分化來支持hESC的長期自我更新的一種模型。
mTOR對bFGF、MEF-CM和KSR等外在因素有反應(yīng)，整合并傳遞多能支持信號。激活mTOR抑制Wnt信號通路，結(jié)合未知機(jī)制（虛線；問號）抑制MIXL1、Brachyury(T基因)、EBF2和PITX2在hESCs中的轉(zhuǎn)錄活性。抑制發(fā)育基因是OCT-4/SOX2/NANOG網(wǎng)絡(luò)穩(wěn)定性所必需的。mTOR還抑制生長抑制分子，包括Cyclin G2和PDCD4，從而促進(jìn)細(xì)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.
參考文獻(xiàn)：https://sci-hub.se/10.1073/pnas.0901854106
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