Magnus Tim, Coksaygan Turhan, Korn Thomas, Xue Haipeng, Arumugam Thiruma V, Mughal Mohamed R, Eckley D Mark, Tang Sung-Chun, Detolla Louis, Rao Mahendra S, Cassiani-Ingoni Riccardo, Mattson Mark P
Laboratory of Neurosciences, National Institute on Aging Intramural Research Program, National Institutes of Health, Baltimore, Maryland 21224, USA.
J Neurosci Res. 2007 Aug 1;85(10):2126-37. doi: 10.1002/jnr.21368.
The mechanisms by which neural and glial progenitor cells in the adult brain respond to tissue injury are unknown. We studied the responses of these cells to stab wound injury in rats and in two transgenic mouse models in which Y/GFP is driven either by Sox2 (a neural stem cell marker) or by Talpha-1 (which marks newly born neurons). The response of neural progenitors was low in all nonneurogenic regions, and no neurogenesis occurred at the injury site. Glial progenitors expressing Olig2 and NG2 showed the greatest response. The appearance of these progenitors preceded the appearance of reactive astrocytes. Surprisingly, we found evidence of the translocation of the transcription factor Olig2 into cytoplasm in the first week after injury, a mechanism that is known to mediate the differentiation of astrocytes during brain development. Translocation of Olig2, down-regulation of NG2, and increased glial fibrillary acidic protein expression were recapitulated in vitro after exposure of glial progenitors to serum components or bone morphogentic protein by up-regulation of Notch-1. The glial differentiation and Olig2 translocation could be blocked by inhibition of Notch-1 with the gamma-secretase inhibitor DAPT. Together, these data indicate that the prompt maturation of numerous Olig2(+) glial progenitors to astrocytes underlies the repair process after a traumatic injury. In contrast, neural stem cells and neuronal progenitor cells appear to play only a minor role in the injured adult CNS.
成人大脑中神经和胶质祖细胞对组织损伤作出反应的机制尚不清楚。我们研究了这些细胞对大鼠刺伤损伤以及两种转基因小鼠模型（其中Y/GFP分别由神经干细胞标志物Sox2或标记新生神经元的Talpha-1驱动）的反应。在所有非神经源性区域，神经祖细胞的反应都很低，并且在损伤部位未发生神经发生。表达Olig2和NG2的胶质祖细胞反应最为强烈。这些祖细胞的出现先于反应性星形胶质细胞的出现。令人惊讶的是，我们发现转录因子Olig2在损伤后第一周向细胞质易位的证据，这是一种已知在脑发育过程中介导星形胶质细胞分化的机制。在胶质祖细胞暴露于血清成分或骨形态发生蛋白后，通过Notch-1的上调，Olig2的易位、NG2的下调和胶质纤维酸性蛋白表达的增加在体外得到重现。用γ-分泌酶抑制剂DAPT抑制Notch-1可阻断胶质细胞分化和Olig2易位。总之，这些数据表明，众多Olig2(+)胶质祖细胞迅速成熟为星形胶质细胞是创伤性损伤后修复过程的基础。相比之下，神经干细胞和神经元祖细胞在受伤的成体中枢神经系统中似乎只起次要作用。
