神經(jīng)干細(xì)胞分化調(diào)控分子機(jī)制以及影響神經(jīng)干細(xì)胞命運(yùn)外在因素的研究對(duì)于神經(jīng)發(fā)育、組織再生,、神經(jīng)系統(tǒng)退行性疾病以及腦腫瘤的發(fā)生發(fā)展和治療都有非常重要的意義,。雖然目前對(duì)神經(jīng)干細(xì)胞增殖分化調(diào)控的研究很多，但是迄今為止,，有關(guān)小分子化合物調(diào)控神經(jīng)元增殖和定向分化的報(bào)道非常少,。
AICAR是一個(gè)AMP類似物，廣泛的用作細(xì)胞水平激活A(yù)MPK的工具化合物,。目前對(duì)其的研究主要集中在代謝調(diào)節(jié)方面,，而其絕大多數(shù)的作用都是通過(guò)激活單磷酸腺苷激活蛋白激酶（AMPK）而發(fā)揮的。AMPK 作為細(xì)胞中的“燃料開(kāi)關(guān)”在動(dòng)物抵御和適應(yīng)環(huán)境應(yīng)激的過(guò)程中起著重要作用,。
該研究首次發(fā)現(xiàn)小分子化合物AICAR對(duì)于生化神經(jīng)干細(xì)胞C17.2及來(lái)源于不同發(fā)展時(shí)期及不同部位來(lái)源的神經(jīng)干細(xì)胞（P0-NSCs及E14-NSCs）均有明顯的誘導(dǎo)分化作用,。通過(guò)對(duì)神經(jīng)元、膠質(zhì)細(xì)胞等標(biāo)志性蛋白的鑒定,，明確了AICAR能定向誘導(dǎo)神經(jīng)干細(xì)胞分化為星形膠質(zhì)細(xì)胞,。有意思的是AMPK的另一個(gè)傳統(tǒng)激活劑二甲雙胍卻沒(méi)有這個(gè)促分化的作用。而過(guò)表達(dá)功能缺失性AMPK等方式也不能逆轉(zhuǎn)AICAR的促膠質(zhì)細(xì)胞定向分化作用,。研究中,，還首次發(fā)現(xiàn)了AICAR能激活與神經(jīng)干細(xì)胞向膠質(zhì)細(xì)胞分化密切相關(guān)的JAK-STAT信號(hào)通路，Metformin則無(wú)法激活該通路,，JAK 特異性抑制劑可完全逆轉(zhuǎn)AICAR的促分化作用,。這些結(jié)果表明，AICAR的定向誘導(dǎo)神經(jīng)干細(xì)胞分化為膠質(zhì)細(xì)胞的作用可能并不依賴于其傳統(tǒng)胞內(nèi)靶點(diǎn)AMPK信號(hào)通路,，而有可能是通過(guò)激活JAK-STAT3信號(hào)通路而起作用的,。
以上結(jié)果已在《生物化學(xué)雜志》（J. Biol. Chem.）雜志上發(fā)表,，為定向誘導(dǎo)神經(jīng)干細(xì)胞分化小分子誘導(dǎo)劑的發(fā)現(xiàn)及神經(jīng)膠質(zhì)細(xì)胞分化機(jī)制研究提供了線索。（生物谷）
生物谷推薦原始出處：
（J. Biol. Chem.）,，Vol. 283, Issue 10, 6201-6208,，Yi Zang，Jia Li
AICAR Induces Astroglial Differentiation of Neural Stem Cells via Activating the JAK/STAT3 Pathway Independently of AMP-activated Protein Kinase*
Yi Zang, Li-Fang Yu, Tao Pang, Lei-Ping Fang, Xu Feng, Tie-Qiao Wen¶, Fa-Jun Nan, Lin-Yin Feng, and Jia Li1
From the National Center for Drug Screening and the Neurological Pharmacology Department, Shanghai Institute of Materia Medica, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 201203 and the ¶School of Life Science, Shanghai University, Shanghai 200444, China
Neural stem cell differentiation and the determination of lineage decision between neuronal and glial fates have important implications in the study of developmental, pathological, and regenerative processes. Although small molecule chemicals with the ability to control neural stem cell fate are considered extremely useful tools in this field, few were reported. AICAR is an adenosine analog and extensively used to activate AMP-activated protein kinase (AMPK), a metabolic "fuel gauge" of the biological system. In the present study, we found an unrecognized astrogliogenic activity of AICAR on not only immortalized neural stem cell line C17.2 (C17.2-NSC), but also primary neural stem cells (NSCs) derived from post-natal (P0) rat hippocampus (P0-NSC) and embryonic day 14 (E14) rat embryonic cortex (E14-NSC). However, another AMPK activator, Metformin, did not alter either the C17.2-NSC or E14-NSC undifferentiated state although both Metformin and AICAR can activate the AMPK pathway in NSC. Furthermore, overexpression of dominant-negative mutants of AMPK in C17.2-NSC was unable to block the gliogenic effects of AICAR. We also found AICAR could activate the Janus kinase (JAK) STAT3 pathway in both C17.2-NSC and E14-NSC but Metformin fails. JAK inhibitor I abolished the gliogenic effects of AICAR. Taken together, these results suggest that the astroglial differentiation effect of AICAR on neural stem cells was acting independently of AMPK and that the JAK-STAT3 pathway is essential for the gliogenic effect of AICAR.
