Department of Neurology, Jinling Hospital, Medical School of Nanjing University, Nanjing, 210002 Jiangsu, China.
University of British Columbia, Kinsmen Laboratory of Neurological Research, Vancouver, British Columbia, Canada.
Oxid Med Cell Longev. 2019 Apr 3;2019:8739730. doi: 10.1155/2019/8739730. eCollection 2019.
Transplantation of neural stem cells (NSCs) is a promising therapy for ischemic stroke. However, the effectiveness of this approach is limited by grafted cell death. Breast cancer susceptibility protein 1 (BRCA1) could suppress apoptosis in neural progenitors and modulate oxidative stress in neurons. In this study, we found that BRCA1 was upregulated by oxygen-glucose deprivation/reoxygenation (OGD/R). Overexpression of BRCA1 in NSCs reduced cell apoptosis and oxidative stress after OGD/R insult. The molecule overexpression also stimulated cellular proliferation in OGD/R NSCs and increased the survival rate of grafted cells. Further, the transplantation of BRCA1-transfected NSCs into mice with ischemic stroke increased brain-derived neurotropic factor and nerve growth factor expression in the brain and elicited neurological function improvement. In addition, we found that RING finger domain and BRCT domain of BRCA1 could physically interact with p53 in NSCs. The cross talk between BRCA1 RING finger domain and p53 was responsible for p53 ubiquitination and degradation. Our findings indicate that modification with BRCA1 could enhance the efficacy of NSCs transplantation in ischemic stroke.
神经干细胞（NSCs）移植是一种有前途的缺血性中风治疗方法。然而，这种方法的效果受到移植物细胞死亡的限制。乳腺癌易感蛋白 1（BRCA1）可以抑制神经祖细胞的凋亡，并调节神经元中的氧化应激。在这项研究中，我们发现 BRCA1 被氧葡萄糖剥夺/复氧（OGD/R）上调。NSCs 中 BRCA1 的过表达可减少 OGD/R 损伤后细胞凋亡和氧化应激。分子过表达还刺激 OGD/R NSCs 中的细胞增殖，并提高移植细胞的存活率。此外，将转染 BRCA1 的 NSCs 移植到缺血性中风小鼠体内，可增加大脑中脑源性神经营养因子和神经生长因子的表达，并改善神经功能。此外，我们发现 BRCA1 的 RING 指结构域和 BRCT 结构域可以在 NSCs 中与 p53 发生物理相互作用。BRCA1 RING 指结构域与 p53 之间的串扰负责 p53 的泛素化和降解。我们的研究结果表明，BRCA1 的修饰可以增强 NSCs 移植治疗缺血性中风的效果。
