Yang Hao, Feng Guo-Dong, Olivera Cathy, Jiao Xi-Ying, Vitale Angela, Gong Ju, You Si-Wei
Institute of Neurosciences, The Fourth Military Medical University, Xi'an, China.
Stem Cell Res. 2012 Sep;9(2):156-66. doi: 10.1016/j.scr.2012.06.002. Epub 2012 Jun 13.
Recent studies demonstrated that mature atrocytes have the capacity for de-differentiating into neural stem/progenitor cells (NSPCs) in vitro and in vivo. However, it is still unknown what signals endow astroglial cells with a de-differentiation potential. Furthermore, the signaling molecules and underlying mechanism that confer astrocytes with the competence of NSPC phenotypes have not been completely elucidated. Here, we found that sonic hedgehog (Shh) production in astrocytes following mechanical injury was significantly elevated, and that incubation of astrocyes with the injured astrocyte conditioned medium (ACM) causes astrocytes to gradually lose their immunophenotypical profiles, and acquire NSPC characteristics, as demonstrated by down-regulation of typical astrocytic markers (GFAP and S100) and up-regulation of markers that are generally expressed in NSCs, (nestin, Sox2, and CD133). ACM treated astrocytes exhibit self-renewal capacity and multipotency similar to NSPCs. Concomitantly, in addition to Ptc, there was a significant up-regulation of the Shh downstream signal components Gli2 and Cyclin D1 which are involved in cell proliferation, dramatic changes in cell morphology, and the disruption of cell-cycle G1 arrest. Conversely, the depletion of Shh by administration of its neutralizing antibody (Shh n-Ab) effectively inhibited the de-differentiation process. Strikingly, Shh alone had little effect on astrocyte de-differentiation to NSPCs. These data above suggest that Shh is a key instructive molecule while other molecules secreted from insulted astrocytes may synergistically promote the de-differentiation event.
最近的研究表明，成熟的星形胶质细胞在体外和体内都有去分化为神经干细胞/祖细胞（NSPCs）的能力。然而，仍不清楚是什么信号赋予星形胶质细胞去分化的潜能。此外，赋予星形胶质细胞NSPC表型能力的信号分子和潜在机制尚未完全阐明。在此，我们发现机械损伤后星形胶质细胞中声波刺猬因子（Shh）的产生显著增加，并且用损伤的星形胶质细胞条件培养基（ACM）培养星形胶质细胞会导致其逐渐丧失免疫表型特征，并获得NSPC特性，这表现为典型星形胶质细胞标志物（GFAP和S100）的下调以及通常在神经干细胞中表达的标志物（巢蛋白、Sox2和CD133）的上调。ACM处理的星形胶质细胞表现出与NSPCs相似的自我更新能力和多能性。同时，除了Patched（Ptc）之外，Shh下游参与细胞增殖的信号成分Gli2和细胞周期蛋白D1也显著上调，细胞形态发生显著变化，细胞周期G1期阻滞被破坏。相反，通过给予其中和抗体（Shh n-Ab）耗尽Shh可有效抑制去分化过程。令人惊讶的是，单独的Shh对星形胶质细胞向NSPCs的去分化几乎没有影响。上述数据表明，Shh是关键的指导分子，而受损星形胶质细胞分泌的其他分子可能协同促进去分化事件。
