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

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

doi:10.1016/j.isci.2025.112302

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. eCollection 2025 May 16.

Authors

Tianyuan Zhang^{1

2

3}, Xiaojuan Zheng⁴, Aijun Lu^{1

2

3}, Shuyuan Li^{1

2

3}, Keshen Li², Xiaoxiong Huang⁵, Yanfang Liu^{1

2

3}, Wei Chen^{1

2

3}, Shengming Huang^{1

2

3}, Niu He¹, Chi Kwan Tsang², Hongcheng Mai⁶, 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.

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.

Keywords: Model organism; Molecular neuroscience.