Abstract WP238: Brain–Thymus–Immune Axis Remodeling after Intracerebral Hemorrhage: Therapeutic Potential of Exosomes

Introduction: Multiple organ dysfunction can occur after intracerebral hemorrhage (ICH), impairing recovery. The thymus, essential for T-cell maturation, undergoes rapid involution with age and injury, accelerating immunosenescence and increasing long-term mortality risk. Although mesenchymal stem cell–derived exosomes (MSC-Exo) show neuroprotective effects in various brain injuries, their potential to restore thymic function via brain–thymus immune-axis after ICH is unknown. We hypothesized that human umbilical cord blood MSC-Exo (HUCB-MSC-Exo) could mitigate ICH-induced thymic injury and immune aging by remodeling the brain–thymus–immune axis. Methods: ICH was induced in 6–8-month-old male mice by intracerebral collagenase injection. Mice received tail-vein HUCB-MSC-Exo or vehicle. Neurological and cognitive outcomes were assessed over 7 days. Brain, thymus, and spleen were analyzed by histology, β-gal staining, immunofluorescence, flow cytometry, and bulk RNA-seq.Endpoints included hemorrhage size, thymus index, cortex/medulla ratio, inflammation, glial activation, iron deposition, cellular senescence, and T-cell developmental profiles. Results: HUCB-MSC-Exo reduced hemorrhage volume, improved neurological and cognitive performance, restored thymus index and cortex/medulla structure, and corrected T-cell developmental defects (reduced double-negative, increased double-positive thymocytes). In the brain, treatment alleviated inflammatory cell infiltration, reduced iron deposition, and normalized glial activation—decreasing M1-like microglia and enhancing M2 polarization. β-gal staining showed reduced senescent cell burden in the brain; RNA-seq revealed that in the brain, 27 genes upregulated after ICH (e.g., Gfap, Cxcl5, Socs3) were downregulated by HUCB-MSC-Exo, with enrichment in JAK–STAT, TNF, and complement/coagulation pathways. In the thymus,156 genes downregulated (e.g., Tcf7, Bcl11b, Themis) after ICH were upregulated post-HUCB-MSC-Exo treatment, affecting T-cell receptor and Th1/Th2/Th17 differentiation pathways. Conclusion: This study identifies brain–thymus–immune axis remodeling as a novel therapeutic target after ICH and provides the first evidence that MSC-Exo can partially reverse ICH-induced thymic dysfunction and T-cell developmental impairment. By mitigating neurovascular injury and modulating thymic immune aging pathways, HUCB-MSC-Exo represents a promising strategy to counter post-ICH immunosenescence and improve systemic recovery.