Duan Qingrui, Li Siyi, Wen Xinrui, Sunnassee Gavin, Chen Jian, Tan Sheng, Guo Yang
Department of Neurology, Zhujiang Hospital, Southern Medical University, Guangzhou, China.
Front Neurosci. 2019 Sep 4;13:867. doi: 10.3389/fnins.2019.00867. eCollection 2019.
Inducing somatic cells into neural stem cells (iNSCs) in specific ways provides a new cell therapy in a variety of neurological diseases. In the past, iNSCs were generated by transcription factors which increased the risk of mutagenesis, tumor formations, and immune reactions by viral transduction vectors. Therefore, in this study, different small molecules were used to induce mouse embryonic fibroblasts (MEFs) into iNSCs in different reprogramming stages, which showed high reprogramming efficiency without altering the genome. We demonstrated that the small molecules staged-induction neural stem cells (SMSINS) have the characteristics of neural stem cells (NSCs) in morphology, gene expression, self-renewal and differentiation potential. Furthermore, valproic acid (VPA), one of small molecules, was showed to enhance neural induction with highest efficiency compared with six other small molecules, which were also investigated in the present study. Moreover, our results suggested that activating the mammalian target of rapamycin (mTOR) signaling enhanced the induction efficiency and neuronal differentiation. Collectively, our findings indicated that using this induction program allowed us to obtain safe and efficient iNSCs which were free of genetic manipulation. The VPA-mediated mTOR signaling pathway may enhance reprogramming efficiency and neuronal differentiation. So we suggested that this program could be a new method of obtaining iNSCs for the treatment of neurological diseases by cell replacement therapy in the future.
以特定方式将体细胞诱导为神经干细胞（iNSCs）为多种神经系统疾病提供了一种新的细胞疗法。过去，iNSCs是通过转录因子产生的，这会增加诱变、肿瘤形成以及病毒转导载体引发免疫反应的风险。因此，在本研究中，使用不同的小分子在不同的重编程阶段将小鼠胚胎成纤维细胞（MEFs）诱导为iNSCs，其显示出高重编程效率且不改变基因组。我们证明，小分子阶段性诱导神经干细胞（SMSINS）在形态、基因表达、自我更新和分化潜能方面具有神经干细胞（NSCs）的特征。此外，与本研究中还研究的其他六种小分子相比，小分子之一丙戊酸（VPA）显示出以最高效率增强神经诱导作用。而且，我们的结果表明激活雷帕霉素哺乳动物靶标（mTOR）信号可提高诱导效率和神经元分化。总体而言，我们的研究结果表明，使用这种诱导方案能够获得安全有效的、无基因操作的iNSCs。VPA介导的mTOR信号通路可能会提高重编程效率和神经元分化。因此，我们认为该方案可能是未来通过细胞替代疗法获得用于治疗神经系统疾病的iNSCs的一种新方法。
