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Meningeal Lymphatic LTBR Deficiency Links Spinal Cord Injury to Secondary Brain Pathology

Year: 2026

Type: article

Abstract: Spinal cord injury (SCI) induces secondary brain pathology, but the mechanisms linking spinal and brain injury remain unclear. Here, we identify meningeal lymphatic dysfunction as a contributor to secondary brain pathology after SCI. In mice, meningeal lymphatic vessels (mLVs) progressively deteriorated from 14 to 56 days post-injury, accompanied by glymphatic dysfunction. In patients with SCI, diffusion tensor imaging along the perivascular space (DTI-ALPS) revealed impaired glymphatic function, which correlated with motor cortical and hippocampal atrophy. mLVs ablation exacerbated neuroinflammation, neuronal loss, impaired hippocampal neurogenesis, and motor and cognitive deficits, whereas VEGF-C-mediated lymphatic restoration ameliorated these abnormalities. Integrated single-cell and bulk transcriptomics identified reduced LTBR expression in meningeal lymphatic endothelial cells (LECs) after SCI. Ltbr knockdown in LECs further exacerbated SCI-induced lymphatic dysfunction and secondary brain pathology, whereas LEC-specific Ltbr overexpression promoted lymphatic repair and improved neurological outcomes. In human LECs, LTBR enhanced proliferation, migration, and tube formation, with PI3K-AKT signaling potentially contributing to these effects. These findings establish meningeal lymphatic dysfunction as an important component of secondary brain pathology after SCI and identify LTBR as a potential regulator of lymphatic repair.

Source: Advanced Science

DOI: 10.1002/advs.78206