Neurobiology of disease · 2025
Endothelial ephrin-B2 knockdown increases post-traumatic disruption of the blood-spinal cord barrier following spinal cord injury.
СтатьяПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод в очереди
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Kersting Katharina, von Bronewski Emily J, Roolfs Laurens T, Meyer Lea, Waldmann Lilly, Nieminen-Kelhä Melina, Kremenetskaia Irina, Nitzsche Anja, Rex Andre, Prüß Harald, Adams Ralf, Heppner Frank L, Fehlings Michael G, Vajkoczy Peter, Hubertus Vanessa
Аннотация
OBJECTIVES: Traumatic Spinal Cord Injury (SCI) disrupts the Blood-Spinal Cord Barrier (BSCB), amplifying injury processes. Targeted therapies require deeper insight into underlying mechanisms. Endothelial Ephrin-B2, a guidance molecule regulating cell adhesion and repulsion, might influence the BSCB, but its role after SCI remains unknown. This study investigates Ephrin-B2 in endothelial cells (ECs) and its influence on BSCB integrity in a mouse SCI model up to 28 days.
METHODS: Transgenic mice with tamoxifen-inducible EC-specific Ephrin-B2 knockdown (efnb2iΔEC, n = 79) and Cre-negative littermates (efnb2lox/lox, n = 71) received serial tamoxifen injections. Animals underwent thoracic clip-compression injury (Th6/7, 60s, 5 g, n = 128) or Sham injury (laminectomy, n = 22). At postoperative days 1, 3, 7, 14 and 28 in vivo analysis included neurological assessment (Basso Mouse Scale, Tally Subscore, CatWalkTM automated gait analysis) and 7 T MRI (T2 Turbo Rare). Ex vivo analysis included Evans Blue assay (n = 5 per group/timepoint), vessel perfusion, and immunohistochemistry (n = 4 per group/timepoint) examining vessel density (CD31, FITC-Lectin), pericyte coverage (CD31, Desmin, PDGFR-beta), and junction proteins (Claudin-5, VE-Cadherin).
RESULTS: efnb2iΔEC mice showed increased BSCB disruption during the acute phase (1d: p = 0.0117; 3d: p = 0.0153) accompanied by a trend for increased edema on day 1 after SCI (p = 0.0712). Vascular and junctional markers revealed posttraumatic impairment with regeneration after day 7, without significant inter-group differences (p > 0.05). Neurological recovery however was not influenced by EC-specific Ephrin-B2 knockdown (p > 0.05).
CONCLUSIONS: Endothelial Ephrin-B2 is crucial for BSCB resilience after SCI. Its EC- specific knockdown aggravates barrier disruption and influences edema volume, suggesting Ephrin-B2 as a potential therapeutic target for acute SCI.
METHODS: Transgenic mice with tamoxifen-inducible EC-specific Ephrin-B2 knockdown (efnb2iΔEC, n = 79) and Cre-negative littermates (efnb2lox/lox, n = 71) received serial tamoxifen injections. Animals underwent thoracic clip-compression injury (Th6/7, 60s, 5 g, n = 128) or Sham injury (laminectomy, n = 22). At postoperative days 1, 3, 7, 14 and 28 in vivo analysis included neurological assessment (Basso Mouse Scale, Tally Subscore, CatWalkTM automated gait analysis) and 7 T MRI (T2 Turbo Rare). Ex vivo analysis included Evans Blue assay (n = 5 per group/timepoint), vessel perfusion, and immunohistochemistry (n = 4 per group/timepoint) examining vessel density (CD31, FITC-Lectin), pericyte coverage (CD31, Desmin, PDGFR-beta), and junction proteins (Claudin-5, VE-Cadherin).
RESULTS: efnb2iΔEC mice showed increased BSCB disruption during the acute phase (1d: p = 0.0117; 3d: p = 0.0153) accompanied by a trend for increased edema on day 1 after SCI (p = 0.0712). Vascular and junctional markers revealed posttraumatic impairment with regeneration after day 7, without significant inter-group differences (p > 0.05). Neurological recovery however was not influenced by EC-specific Ephrin-B2 knockdown (p > 0.05).
CONCLUSIONS: Endothelial Ephrin-B2 is crucial for BSCB resilience after SCI. Its EC- specific knockdown aggravates barrier disruption and influences edema volume, suggesting Ephrin-B2 as a potential therapeutic target for acute SCI.