中国神经再生研究(英文版) ›› 2024, Vol. 19 ›› Issue (8): 1772-1780.doi: 10.4103/1673-5374.389303

• 原著:脑损伤修复保护与再生 • 上一篇    下一篇

高频重复经颅磁刺激促进缺血性脑卒中后神经干细胞增殖

  

  • 出版日期:2024-08-15 发布日期:2024-01-03
  • 基金资助:
    国家自然科学基金项目(81672261,81972151,82372568);广东省自然科学基金项目(2019A1515011106,2023A1515030080)

High-frequency repetitive transcranial magnetic stimulation promotes neural stem cell proliferation after ischemic stroke

Jing Luo1, #, Yuan Feng2, #, Zhongqiu Hong1, Mingyu Yin1, Haiqing Zheng1, Liying Zhang1, *, Xiquan Hu1, *   

  1. 1Department of Rehabilitation Medicine, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong Province, China; 2Department of Hepatobiliary Surgery, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong Province, China
  • Online:2024-08-15 Published:2024-01-03
  • Contact: Xiquan Hu, MD, huxiquan@mail.sysu.edu.cn; Liying Zhang, MD, zhangly29@mail.sysu.edu.cn.
  • Supported by:
    This study was supported by the National Natural Science Foundation of China, Nos. 81672261 (to XH), 81972151 (to HZ), 82372568 (to JL); the Natural Science Foundation of Guangdong Province, Nos. 2019A1515011106 (to HZ), 2023A1515030080 (to JL).

摘要:

神经干细胞增殖对于促进神经元再生和修复脑梗死损伤具有重要意义。重复性经颅磁刺激最近成为诱导内源性神经干细胞再生的工具之一,但其潜在机制尚不清楚。此次实验发现,重复性磁刺激可有效促进氧糖剥夺神经干细胞的增殖,且重复性经颅磁刺激可减少大脑总动脉闭塞致缺血性脑卒中大鼠模型脑梗死体积,改善其认知功能,促进缺血半暗带中神经干细胞的增殖。进一步RNA测序显示重复性经颅磁刺激可激活脑缺血大鼠缺血半暗带中Wnt信号通路。进一步PCR分析表明,重复经颅磁刺激可通过促进Akt磷酸化,上调调节细胞周期蛋白的表达,激活糖原合成酶激酶3β/β-catenin通路,从而促进糖原合成酶激酶的增殖。最后对重复经颅磁刺激影响ATK磷酸化进行验证,发现重复经颅磁刺激可通过激活P2通道/CaM通路促进神经干细胞中Ca2+的流入,从而促进Akt的磷酸化并激活糖原合成酶激酶3β/β-catenin通路。由此提示,重复经颅磁刺激可通过钙离子内流调控的磷酸化AKT/糖原合成酶激酶3β/β-catenin信号通路来发挥促进内源性神经干细胞增殖的作用。该研究得到了重复经颅磁刺激促进缺血性脑卒中后神经功能恢复内在机制的开拓性成果,其结果可为重复经颅磁刺激临床治疗提供新的科学理论依据。

https://orcid.org/0000-0002-5554-6903 (Xiquan Hu); https://orcid.org/0000-0002-9969-4561 (Liying Zhang)

关键词: 神经干细胞, 高频重复经颅磁刺激, 缺血性脑卒中, 大脑中动脉闭塞, 细胞增殖, Ca2+内流, 神经康复, 脑刺激, AKT, β-catenin

Abstract: Proliferation of neural stem cells is crucial for promoting neuronal regeneration and repairing cerebral infarction damage. Transcranial magnetic stimulation (TMS) has recently emerged as a tool for inducing endogenous neural stem cell regeneration, but its underlying mechanisms remain unclear. In this study, we found that repetitive TMS effectively promotes the proliferation of oxygen-glucose deprived neural stem cells. Additionally, repetitive TMS reduced the volume of cerebral infarction in a rat model of ischemic stroke caused by middle cerebral artery occlusion, improved rat cognitive function, and promoted the proliferation of neural stem cells in the ischemic penumbra. RNA-sequencing found that repetitive TMS activated the Wnt signaling pathway in the ischemic penumbra of rats with cerebral ischemia. Furthermore, PCR analysis revealed that repetitive TMS promoted AKT phosphorylation, leading to an increase in mRNA levels of cell cycle-related proteins such as Cdk2 and Cdk4. This effect was also associated with activation of the glycogen synthase kinase 3β/β-catenin signaling pathway, which ultimately promotes the proliferation of neural stem cells. Subsequently, we validated the effect of repetitive TMS on AKT phosphorylation. We found that repetitive TMS promoted Ca2+ influx into neural stem cells by activating the P2 calcium channel/calmodulin pathway, thereby promoting AKT phosphorylation and activating the glycogen synthase kinase 3β/β-catenin pathway. These findings indicate that repetitive TMS can promote the proliferation of endogenous neural stem cells through a Ca2+ influx-dependent phosphorylated AKT/glycogen synthase kinase 3β/β-catenin signaling pathway. This study has produced pioneering results on the intrinsic mechanism of repetitive TMS to promote neural function recovery after ischemic stroke. These results provide a strong scientific foundation for the clinical application of repetitive TMS. Moreover, repetitive TMS treatment may not only be an efficient and potential approach to support neurogenesis for further therapeutic applications, but also provide an effective platform for the expansion of neural stem cells.

Key words: AKT/β-catenin signaling, brain stimulation, Ca2+ influx, cell proliferation, ischemic stroke, middle cerebral artery occlusion, neural stem cells, neurological rehabilitation, repetitive transcranial magnetic stimulation