Humanized mouse model reveals T cell ANXA2 as a potential therapeutic target in ischemic stroke

IF 4.6 2区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES

iScience Pub Date : 2025-04-02 DOI:10.1016/j.isci.2025.112302

Tianyuan Zhang , Xiaojuan Zheng , Aijun Lu , Shuyuan Li , Keshen Li , Xiaoxiong Huang , Yanfang Liu , Wei Chen , Shengming Huang , Niu He , Chi Kwan Tsang , Hongcheng Mai , Anding Xu , Dan Lu

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Abstract

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_CM and T_EM 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.

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人源化小鼠模型揭示T细胞ANXA2是缺血性脑卒中的潜在治疗靶点

在啮齿类动物中的中风T细胞研究尚未转化为人类研究。中风后细胞和分子T细胞变化的机制尚不完全清楚。因此，本研究建立了大脑中动脉闭塞（MCAO）后人源化小鼠模型，并确定了人源化T细胞群的潜在治疗靶点。与中风患者相似，人源化T细胞中风小鼠外周血中T细胞比例降低。通过单细胞RNA测序（scRNA-seq），我们确定了Annexin A2 （ANXA2）作为MCAO人源化T细胞亚群的生物标志物，并在人缺血脑和外周血中进行了验证。使用小分子抑制剂Leu-Cys-Lys-Leu-Ser-Leu (LCKLSL)， ANXA2抑制改变了人源化小鼠的TCM和TEM亚群。此外，LCKLSL还具有抗缺血性损伤、减轻神经炎症、抑制T细胞浸润和降低促炎因子的神经保护作用。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。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

iScience Multidisciplinary-Multidisciplinary

CiteScore

7.20

自引率

1.70%

发文量

1972

审稿时长

6 weeks

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