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

  • iScience. 2025 Apr 2;28(5):112302. doi: 10.1016/j.isci.2025.112302.
Tianyuan Zhang  1  2  3 ,  Xiaojuan Zheng  4 ,  Aijun Lu  1  2  3 ,  Shuyuan Li  1  2  3 ,  Keshen Li  2 ,  Xiaoxiong Huang  5 ,  Yanfang Liu  1  2  3 ,  Wei Chen  1  2  3 ,  Shengming Huang  1  2  3 ,  Niu He  1 ,  Chi Kwan Tsang  2 ,  Hongcheng Mai  6 ,  Anding Xu  1  2  3 ,  Dan Lu  1  2  3
Affiliations
  • 1. Department of Neurology and Stroke Center, The First Affiliated Hospital of Jinan University, Guangzhou 510632, China.
  • 2. Clinical Neuroscience Institute, The First Affiliated Hospital of Jinan University, Guangzhou 510632, China.
  • 3. Key Lab of Guangzhou Basic and Translational Research of Pan-vascular Diseases, The First Affiliated Hospital of Jinan University, Guangzhou 510632, China.
  • 4. Department of Dermatology, The First Affiliated Hospital of Jinan University, Guangzhou 510632, China.
  • 5. Department of Neurology and Stroke Center, The Central Hospital of Shaoyang, Shaoyang 422099, China.
  • 6. Department of Neurology, Sun Yat-Sen MemorialHospital, Sun Yat-Sen University, Guangzhou 510120, China.
PMID: 40641552 DOI: 10.1016/j.isci.2025.112302
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 TCM and TEM 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.

Keywords
Model organism; Molecular neuroscience.
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