神经干细胞分化调控分子机制以及影响神经干细胞命运外在因素的研究对于神经发育、组织再生、神经系统退行性疾病以及脑肿瘤的发生发展和治疗都有非常重要的意义。虽然目前对神经干细胞增殖分化调控的研究很多，但是迄今为止，有关小分子化合物调控神经元增殖和定向分化的报道非常少。
AICAR是一个AMP类似物，广泛的用作细胞水平激活AMPK的工具化合物。目前对其的研究主要集中在代谢调节方面，而其绝大多数的作用都是通过激活单磷酸腺苷激活蛋白激酶（AMPK）而发挥的。AMPK 作为细胞中的“燃料开关”在动物抵御和适应环境应激的过程中起着重要作用。
该研究首次发现小分子化合物AICAR对于生化神经干细胞C17.2及来源于不同发展时期及不同部位来源的神经干细胞（P0-NSCs及E14-NSCs）均有明显的诱导分化作用。通过对神经元、胶质细胞等标志性蛋白的鉴定，明确了AICAR能定向诱导神经干细胞分化为星形胶质细胞。有意思的是AMPK的另一个传统激活剂二甲双胍却没有这个促分化的作用。而过表达功能缺失性AMPK等方式也不能逆转AICAR的促胶质细胞定向分化作用。研究中，还首次发现了AICAR能激活与神经干细胞向胶质细胞分化密切相关的JAK-STAT信号通路，Metformin则无法激活该通路，JAK 特异性抑制剂可完全逆转AICAR的促分化作用。这些结果表明，AICAR的定向诱导神经干细胞分化为胶质细胞的作用可能并不依赖于其传统胞内靶点AMPK信号通路，而有可能是通过激活JAK-STAT3信号通路而起作用的。
以上结果已在《生物化学杂志》（J. Biol. Chem.）杂志上发表，为定向诱导神经干细胞分化小分子诱导剂的发现及神经胶质细胞分化机制研究提供了线索。（生物谷）
生物谷推荐原始出处：
（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.
