Zhang Tianyuan, Zheng Xiaojuan, Lu Aijun, Li Shuyuan, Li Keshen, Huang Xiaoxiong, Liu Yanfang, Chen Wei, Huang Shengming, He Niu, Tsang Chi Kwan, Mai Hongcheng, Xu Anding, Lu Dan
Department of Neurology and Stroke Center, The First Affiliated Hospital of Jinan University, Guangzhou 510632, China.
Clinical Neuroscience Institute, The First Affiliated Hospital of Jinan University, Guangzhou 510632, China.
iScience. 2025 Apr 2;28(5):112302. doi: 10.1016/j.isci.2025.112302. eCollection 2025 May 16.
Stroke T cell studies in rodents have not been translated to human studies. The mechanism of cellular and molecular T cells changes after stroke remains incompletely understood. Thus, this study established a humanized mouse model after middle cerebral artery occlusion (MCAO) and identifies potential therapeutic targets of humanized T cell populations. Similar to patients with stroke, a proportion of T cells was decreased in peripheral blood of humanized T cell stroke mice. Using single-cell RNA sequencing (scRNA-seq), we identified Annexin A2 (ANXA2) as biomarker of humanized T cell subsets in MCAO, which was validated using human ischemic brain and peripheral blood. With small-molecule inhibitors Leu-Cys-Lys-Leu-Ser-Leu (LCKLSL), ANXA2 inhibition altered T and T subset in humanized mice. Furthermore, LCKLSL exhibited a neuroprotective role against ischemic damage, mitigating neuroinflammation, inhibiting T cell infiltration, and decreasing pro-inflammatory factors. Hence, this humanized T cell ischemic stroke model is more representative of the human disease than previous models; furthermore, ANXA2 is a meaningful therapeutic target.
在啮齿动物中进行的中风T细胞研究尚未转化为人体研究。中风后细胞和分子水平T细胞变化的机制仍未完全了解。因此，本研究建立了大脑中动脉闭塞（MCAO）后的人源化小鼠模型，并确定了人源化T细胞群体的潜在治疗靶点。与中风患者相似，人源化T细胞中风小鼠外周血中的一部分T细胞减少。使用单细胞RNA测序（scRNA-seq），我们确定膜联蛋白A2（ANXA2）为MCAO中人源化T细胞亚群的生物标志物，这在人类缺血性脑和外周血中得到了验证。使用小分子抑制剂亮氨酸-半胱氨酸-赖氨酸-亮氨酸-丝氨酸-亮氨酸（LCKLSL），对ANXA2的抑制改变了人源化小鼠中的T细胞和T细胞亚群。此外，LCKLSL对缺血性损伤具有神经保护作用，减轻神经炎症，抑制T细胞浸润，并减少促炎因子。因此，这种人源化T细胞缺血性中风模型比以前的模型更能代表人类疾病；此外，ANXA2是一个有意义的治疗靶点。
