Overexpression of BRCA1 in Neural Stem Cells Enhances Cell Survival and Functional Recovery after Transplantation into Experimental Ischemic Stroke
Overexpression of BRCA1 in Neural Stem Cells Enhances Cell Survival and Functional Recovery after Transplantation into Experimental Ischemic Stroke
复制标题
神经干细胞中 BRCA1 的过度表达可增强移植至实验性缺血性中风后的细胞存活率和功能恢复
DOI：
10.1155/2019/8739730
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发表时间：
2019
影响因子：
--
通讯作者：
Xu Gelin
中科院分区：
文献类型：
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作者：
Xu Pengfei;Shi Xiaolei;Zhang Xiaohao;Liu Qian;Xie Yi;Hong Ye;Li Juanji;Peng Mengna;Liu Xinfeng;Xu Gelin
神经干细胞（NSC）移植是治疗缺血性中风的一种有前途的疗法。然而，这种方法的有效性受到移植细胞死亡的限制。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的氧化应激。在这项研究中，我们发现 BRCA1 通过氧糖剥夺/复氧 (OGD/R) 上调。 NSC 中 BRCA1 的过度表达减少了 OGD/R 损伤后的细胞凋亡和氧化应激。该分子过表达还刺激 OGD/R NSC 的细胞增殖，并提高移植细胞的存活率。此外，将 BRCA1 转染的 NSC 移植到缺血性中风小鼠体内，可以增加大脑中脑源性神经营养因子和神经生长因子的表达，从而改善神经功能。此外，我们发现BRCA1的RING指结构域和BRCT结构域可以与NSC中的p53物理相互作用。 BRCA1 RING Finger 结构域和 p53 之间的串扰导致了 p53 泛素化和降解。我们的研究结果表明，BRCA1 修饰可以增强 NSC 移植治疗缺血性中风的疗效。
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.