Jiangsu Key Laboratory of Xenotransplantation, Nanjing Medical University, Nanjing, People's Republic of China.
Huaian First Hospital Affiliated to Nanjing Medical University, Huai'an, People's Republic of China.
J Neurosci Res. 2018 Jan;96(1):87-102. doi: 10.1002/jnr.24096. Epub 2017 Jun 22.
Ischemic stroke is a devastating neurological disorder and one of the leading causes of death and serious disability in adults. Adult neural stem cell (NSC) replacement therapy is a promising treatment for both structural and functional neurological recovery. However, for the treatment to work, adult NSCs must be protected against hypoxic-ischemic damage in the ischemic penumbra. In the present study, we aimed to investigate the neuroprotective effects of the mfat-1 transgene on cobalt chloride (CoCl )-induced hypoxic-ischemic injury in cultured adult NSCs as well as its underlying mechanisms. The results show that in the CoCl -induced hypoxic-ischemic injury model, the mfat-1 transgene enhanced the viability of adult NSCs and suppressed CoCl -mediated apoptosis of adult NSCs. Additionally, the mfat-1 transgene promoted the proliferation of NSCs as shown by increased bromodeoxyuridine labeling of adult NSCs. This process was related to the reduction of reactive oxygen species. Quantitative real-time polymerase chain reaction and Western blot analysis revealed a much higher expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and its downstream genes (HO-1, NQO-1, GCLC). Taken together, our findings show that the mfat-1 transgene restored the CoCl -inhibited viability and proliferation of NSCs by activating nuclear factor erythroid 2-related factor 2 (Nrf2)/antioxidant response elements (ARE) signal pathway to inhibit oxidative stress injury. Further investigation of the function of the mfat-1 transgene in adult protective mechanisms may accelerate the development of adult NSC replacement therapy for ischemic stroke.
缺血性中风是一种严重的神经疾病，也是成年人死亡和严重残疾的主要原因之一。成体神经干细胞（NSC）替代疗法是一种有前途的治疗结构性和功能性神经恢复的方法。然而，为了使治疗有效，成体 NSCs 必须免受缺血半影区缺氧缺血损伤。在本研究中，我们旨在研究 mfat-1 转基因对氯化钴（CoCl ）诱导的培养成体 NSCs 缺氧缺血损伤的神经保护作用及其潜在机制。结果表明，在 CoCl 诱导的缺氧缺血损伤模型中，mfat-1 转基因增强了成体 NSCs 的活力，并抑制了 CoCl 介导的成体 NSCs 凋亡。此外，mfat-1 转基因促进了 NSCs 的增殖，表现为成体 NSCs 的溴脱氧尿苷标记增加。这个过程与活性氧的减少有关。实时定量聚合酶链反应和 Western blot 分析显示核因子红细胞 2 相关因子 2（Nrf2）及其下游基因（HO-1、NQO-1、GCLC）的表达明显升高。总之，我们的研究结果表明，mfat-1 转基因通过激活核因子红细胞 2 相关因子 2（Nrf2）/抗氧化反应元件（ARE）信号通路抑制氧化应激损伤，恢复了 CoCl 抑制的 NSCs 活力和增殖。进一步研究 mfat-1 转基因在成体保护机制中的功能可能会加速缺血性中风成体 NSC 替代治疗的发展。
