中国神经再生研究(英文版)

中国神经再生研究(英文版) ›› 2023, Vol. 18 ›› Issue (3): 618-625.doi: 10.4103/1673-5374.350207

• 原著:脑损伤修复保护与再生 • 上一篇    下一篇

神经调节素1β预处理神经干细胞对氧糖剥夺/复氧细胞的神经保护作用

  

  • 出版日期:2023-03-15 发布日期:2022-08-28
  • 基金资助:

    中国国家自然科学基金项目（81973501）；山东省自然科学基金项目（ZR2019MH009）

Neuroprotective effects of neural stem cells pretreated with neuregulin1β on PC12 cells exposed to oxygen-glucose deprivation/reoxygenation

Qiu-Yue Zhai1, Yuan-Hua Ye2, Yu-Qian Ren1, Zhen-Hua Song1, Ke-Li Ge1, Bao-He Cheng3, Yun-Liang Guo1, *   

  1. 1Institute of Cerebrovascular Diseases, Medical Research Center, The Affiliated Hospital of Qingdao University, Taishan Scholars Construction Project Excellent Innovative Team of Shandong Province, Qingdao, Shandong Province, China; 2Department of Obstetrics, The Affiliated Hospital of Qingdao University, Qingdao, Shandong Province, China; 3Research Center of Stem Cells, Shandong Haoyun International Hospital of Stem Cells, Jinan, Shandong Province, China
  • Online:2023-03-15 Published:2022-08-28
  • Contact: Yun-Liang Guo, PhD, guoqdsd@qdu.edu.cn.
  • Supported by:
    This work was supported by the National Natural Science Foundation of China, No. 81973501, and the Natural Science Foundation of Shandong Province, No. ZR2019MH009 (both to YLG).

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摘要：

人神经干细胞难以获得且移植后的外源神经干细胞存活率、分化率和增殖率低限制了其临床应用。作者既往研究发现，神经调节素1β可减轻大鼠的脑缺血再灌注损伤。因此作者拟在人脐带间充质干细胞向神经干细胞诱导过程中添加神经调节素1β，可见5 和 10 nM神经调节素1β可促进神经干细胞的形成和增殖，且10 nM的效果更为明显。进而以Transwell共培养系统共培养此种神经干细胞和氧糖剥夺/复氧损伤的PC12细胞，发现神经调节素1β预处理的神经干细胞在一定程度上可降低损伤PC12细胞活性氧、丙二醛、谷胱甘肽、超氧化物歧化酶和NADPH/NADP+含量以及线粒体损伤，降低铁死亡水平。而后以RNA干扰方法敲低神经干细胞中的SLC7A11后，共培养后的损伤PC12细胞中p53表达增加，而谷胱甘肽过氧化物酶4水平增加。由此提示，神经调节素1β预处理的神经干细胞可通过调控与铁死亡有关的p53/谷胱甘肽过氧化物酶4/SLC7A11通路对氧糖剥夺/复氧PC12细胞产生神经保护作用。

https://orcid.org/0000-0002-4797-7615 (Yun-Liang Guo); https://orcid.org/0000-0002-5954-1923 (Qiu-Yue Zhai)

关键词: 神经调节素1β, 人脐带间充质干细胞, 神经干细胞, PC12细胞, 氧糖剥夺/复氧, 铁死亡, 神经保护, p53, SLC7A11, 谷胱甘肽过氧化物酶4

Abstract: Studies on ischemia/reperfusion (I/R) injury suggest that exogenous neural stem cells (NSCs) are ideal candidates for stem cell therapy reperfusion injury. However, NSCs are difficult to obtain owing to ethical limitations. In addition, the survival, differentiation, and proliferation rates of transplanted exogenous NSCs are low, which limit their clinical application. Our previous study showed that neuregulin1β (NRG1β) alleviated cerebral I/R injury in rats. In this study, we aimed to induce human umbilical cord mesenchymal stem cells into NSCs and investigate the improvement effect and mechanism of NSCs pretreated with 10 nM NRG1β on PC12 cells injured by oxygen-glucose deprivation/reoxygenation (OGD/R). Our results found that 5 and 10 nM NRG1β promoted the generation and proliferation of NSCs. Co-culture of NSCs and PC12 cells under condition of OGD/R showed that pretreatment of NSCs with NRG1β improved the level of reactive oxygen species, malondialdehyde, glutathione, superoxide dismutase, nicotinamide adenine dinucleotide phosphate, and nuclear factor erythroid 2-related factor 2 (Nrf2) and mitochondrial damage in injured PC12 cells; these indexes are related to ferroptosis. Research has reported that p53 and solute carrier family 7 member 11 (SLC7A11) play vital roles in ferroptosis caused by cerebral I/R injury. Our data show that the expression of p53 was increased and the level of glutathione peroxidase 4 (GPX4) was decreased after RNA interference-mediated knockdown of SLC7A11 in PC12 cells, but this change was alleviated after co-culturing NSCs with damaged PC12 cells. These findings suggest that NSCs pretreated with NRG1β exhibited neuroprotective effects on PC12 cells subjected to OGD/R through influencing the level of ferroptosis regulated by p53/SLC7A11/GPX4 pathway.

Key words: ferroptosis, p53, SLC7A11, GPX4, human umbilical cord-mesenchymal stem cells, neural stem cells, neuregulin1β, neuroprotection, oxygen-glucose deprivation/reoxygenation, PC12 cell