中国神经再生研究(英文版) ›› 2023, Vol. 18 ›› Issue (7): 1521-1526.doi: 10.4103/1673-5374.357910

• 原著:脑损伤修复保护与再生 • 上一篇    下一篇

Sox2+星形胶质细胞在缺血大脑皮质中的短暂性神经发生

  

  • 出版日期:2023-07-15 发布日期:2023-01-12
  • 基金资助:
    国家自然科学基金;北京市科技新星计划-科技新星

Transient neurogenesis in ischemic cortex from Sox2+ astrocytes

Jia-Lei Yang1, 2, #, Hong Fan1, 3, #, Fan-Fan Fu1, #, Bao-Lin Guo1, Ying Huang4, Li Sun1, Wen-Ting Wang1, Jun-Ling Xing1, Xin-Tian Hu5, Yu-Qiang Ding4, Kun Zhang1, *, Ying-Zhou Hu5, *, Ya-Zhou Wang1, *#br#   

  1. 1Department of Neurobiology and Institute of Neurosciences, School of Basic Medicine, Fourth Military Medical University, Xi’an, Shaanxi Province, China; 2China National Clinical Research Center for Neurological Diseases, Department of Neurology, Beijing Tiantan Hospital, Beijing, China; 3Department of Neurology, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi Province, China; 4State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institute of Brain Science, Fudan University, Shanghai, China; 5Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences & Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan Province, China
  • Online:2023-07-15 Published:2023-01-12
  • Contact: Ya-Zhou Wang, PhD, yazhouw@fmmu.edu.cn; Ying-Zhou Hu, PhD, huyingzhou@mail.kiz.ac.cn; Kun Zhang, PhD, Kunyang1028@126.com.
  • Supported by:
    This work was supported by the National Natural Science Foundation of China, Nos. 82171346 (to YZW), 82171269 (to JLY), 82171471 (to HF); Beijing Nova Program, No. Z201100006820076 (to JLY).

摘要:

长期以来,脑损伤后皮质是否有原位神经元发生一直是研究者争论的问题。目前的主流观点认为,脑缺血后皮质几乎无神经元发生,因为多个研究组未在缺血皮质找到新生成熟神经元。大多数学者认为,如果有,新生神经元应来自侧脑室下区的神经干细胞。本研究发现,在常用的光化学致脑缺血模型中,损伤区皮质快速出现新生幼稚神经元,但绝大多数新生神经元很快死亡。更换损伤轻微的微小脑缺血模型,可以发现新生成熟神经元。进而,通过逆转录病毒标记、遗传学细胞命运追踪等方法,他们发现:侧脑室下区的神经干细胞仅贡献小部分新生神经元,大多数新生神经元来自皮质星形胶质细胞的一个亚群----Sox2阳性星形胶质细胞。皮质的少突胶质前体细胞不产生神经元。最后,他们在猕猴的皮质缺血模型中,也观察到了类似现象。此研究提示大脑皮质的Sox2阳性星形胶质细胞可能具有神经元发生潜能,动员这群细胞有望为脑卒中等疾病的治疗带来新的启示。

https://orcid.org/0000-0002-7116-2395 (Ya-Zhou Wang); 

https://orcid.org/0000-0001-7220-7607 (Ying-Zhou Hu); 

https://orcid.org/0000-0003-2928-8178 (Kun Zhang)

Abstract: The adult cortex has long been regarded as non-neurogenic. Whether injury can induce neurogenesis in the adult cortex is still controversial. Here, we report that focal ischemia stimulates a transient wave of local neurogenesis. Using 5′-bromo-2′-deoxyuridine labeling, we demonstrated a rapid generation of doublecortin-positive neuroblasts that died quickly in mouse cerebral cortex following ischemia. Nestin-CreER-based cell ablation and fate mapping showed a small contribution of neuroblasts by subventricular zone neural stem cells. Using a mini-photothrombotic ischemia mouse model and retrovirus expressing green fluorescent protein labeling, we observed maturation of locally generated new neurons. Furthermore, fate tracing analyses using PDGFRα-, GFAP-, and Sox2-CreER mice showed a transient wave of neuroblast generation in mild ischemic cortex and identified that Sox2-positive astrocytes were the major neurogenic cells in adult cortex. In addition, a similar upregulation of Sox2 and appearance of neuroblasts were observed in the focal ischemic cortex of Macaca mulatta. Our findings demonstrated a transient neurogenic response of Sox2-positive astrocytes in ischemic cortex, which suggests the possibility of inducing neuronal regeneration by amplifying this intrinsic response in the future.  

Key words: adult, astrocyte, cortex, fate-mapping, ischemia, local neurogenesis, neural stem cells, Sox2