Fan Hong, Yang Jialei, Zhang Kun, Xing Junling, Guo Baolin, Mao Honghui, Wang Wenting, Hu Yingzhou, Lin Wei, Huang Ying, Ding Jian, Yu Caiyong, Fu Fanfan, Sun Li, Wu Jing, Zhao Youyi, Deng Wenbin, Zhou Chengji, Qiu Mengsheng, Wu Shengxi, Ding Yu-Qiang, Wang Yazhou
Department of Neurobiology and Institute of Neurosciences, School of Basic Medicine, Fourth Military Medical University, 169 Chang Le Xi Road, Xi'an, Shaanxi, 710032, China.
Department of Neurology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, 710004, China.
NPJ Regen Med. 2022 Sep 2;7(1):42. doi: 10.1038/s41536-022-00248-1.
Reactive astrogliosis usually bears some properties of neural progenitors. How injury triggers astrocyte dedifferentiation remains largely unclear. Here, we report that ischemia induces rapid up-regulation of Wnt2 protein in apoptotic neurons and activation of canonical Wnt signaling in reactive astrocytes in mice, primates and human. Local delivery of Wnt2 shRNA abolished the dedifferentiation of astrocytes while over-expressing Wnt2 promoted progenitor marker expression and neurogenesis. Both the activation of Wnt signaling and dedifferentiation of astrocytes was compromised in ischemic caspase-3 cortex. Over-expressing stabilized β-catenin not only facilitated neurogenesis but also promoted functional recovery in ischemic caspase-3 mice. Further analysis showed that apoptotic neurons up-regulated Wnt2 protein via internal ribosome entry site (IRES)-mediated translation. Knocking down death associated protein 5 (DAP5), a key protein in IRES-mediated protein translation, significantly diminished Wnt activation and astrocyte dedifferentiation. Our data demonstrated an apoptosis-initiated Wnt-activating mechanism which triggers astrocytic dedifferentiation and facilitates neuronal regeneration.
反应性星形胶质细胞增生通常具有一些神经祖细胞的特性。损伤如何触发星形胶质细胞去分化在很大程度上仍不清楚。在此，我们报告，在小鼠、灵长类动物和人类中，缺血诱导凋亡神经元中Wnt2蛋白快速上调，并激活反应性星形胶质细胞中的经典Wnt信号通路。局部递送Wnt2短发夹RNA可消除星形胶质细胞的去分化，而过度表达Wnt2则促进祖细胞标志物表达和神经发生。在缺血性caspase-3皮质中，Wnt信号的激活和星形胶质细胞的去分化均受到损害。过度表达稳定的β-连环蛋白不仅促进神经发生，还促进缺血性caspase-3小鼠的功能恢复。进一步分析表明，凋亡神经元通过内部核糖体进入位点（IRES）介导的翻译上调Wnt2蛋白。敲低死亡相关蛋白5（DAP5），这是IRES介导的蛋白质翻译中的关键蛋白，可显著减少Wnt激活和星形胶质细胞去分化。我们的数据证明了一种由凋亡引发的Wnt激活机制，该机制触发星形胶质细胞去分化并促进神经元再生。
