Sonic Hedgehog Effectively Improves Oct4-Mediated Reprogramming of Astrocytes into Neural Stem Cells
Sonic Hedgehog Effectively Improves Oct4-Mediated Reprogramming of Astrocytes into Neural Stem Cells
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Sonic Hedgehog 有效改善 Oct4 介导的星形胶质细胞重编程为神经干细胞
DOI：
10.1016/j.ymthe.2019.05.006
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发表时间：
2019
影响因子：
12.4
通讯作者：
Hao Dingjun
中科院分区：
文献类型：
--
作者：
Yang Hao;Liu Cuicui;Fan Hong;Chen Bo;Huang Dageng;Zhang Lingling;Zhang Qian;An Jing;Zhao Jingjing;Wang Yi;Hao Dingjun
Irreversible neuron loss following spinal cord injury (SCI) usually results in persistent neurological dysfunction. The generation of autologous neural stem cells (NSCs) holds great potential for neural replenishment therapies and drug screening in SCI. Our recent studies demonstrated that mature astrocytes from the spinal cord can directly revert back to a pluripotent state under appropriate signals. However, in previous attempts, the reprogramming of astrocytes into induced NSCs (iNSCs) was unstable, inefficient, and frequently accompanied by generation of intermediate precursors. It remained unknown how to further increase the efficiency of astrocyte reprogramming into iNSCs. Here, we show that mature astrocytes could be directly converted into iNSCs by a single transcription factor, Oct4, and that the iNSCs displayed typical neurosphere morphology, authentic NSC gene expression, self-renewal capacity, and multipotency. Strikingly, Oct4-driven reprogramming of astrocytes into iNSCs was potentiated with continuous sonic hedgehog (Shh) stimulation, as demonstrated by a sped-up reprogramming and increased conversion efficiency. Moreover, the iNSC-derived neurons possessed functionality as neurons. Importantly, crosstalk between Sox2/Shh-targeted downstream signals and phosphatidylinositol 3-kinase/cyclin-dependent kinase 2/Smad ubiquitin regulatory factor 2 (PI3K/Cdk2/Smurf2) signaling is likely involved in the mechanisms underlying this cellular event. The highly efficient reprogramming of astrocytes to generate iNSCs will provide an alternative therapeutic approach for SCI using autologous cells.
