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

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.