Early Single-Dose Treatment with Exosomes Provides Neuroprotection and Improves Blood-Brain Barrier Integrity in Swine Model of Traumatic Brain Injury and Hemorrhagic Shock
Williams AM, Bhatti UF, Brown JF, Biesterveld BE, Kathawate RG, Graham NJ, Chtraklin K, Siddiqui AZ, Dekker SE, Andjelkovic A, Higgins GA, Buller B, and Alam HB. Early Single-Dose Treatment with Exosomes Provides Neuroprotection and Improves Blood-Brain Barrier Integrity in Swine Model of Traumatic Brain Injury and Hemorrhagic Shock. J Trauma Acute Care Surg 2019.
J Trauma Acute Care Surg
BACKGROUND: Administration of human mesenchymal stem cell (MSC)-derived exosomes can enhance neurorestoration in models of traumatic brain injury (TBI) and hemorrhagic shock (HS). The impact of early treatment with MSC-derived exosomes on brain injury in a large animal model remains unknown. We sought to evaluate the impact of early single-dose exosome treatment on brain swelling and lesion size, blood-based cerebral biomarkers, and blood-brain barrier (BBB) integrity. METHODS: Female Yorkshire swine were subjected to a severe TBI (12-mm cortical impact) and HS (40% estimated total blood volume). One hour into shock, animals were randomized (n=5/cohort) to receive either lactated Ringer's (LR; 5mL) or LR + exosomes (LR+EXO; 1 x 10 exosome particles in 5 mL LR). Animals then underwent additional shock (1 hr) followed by normal saline resuscitation. After 6 hours of observation, brain swelling (% increase compared to the uninjured side) and lesion size (mm) were assessed. Cerebral hemodynamics and blood-based biomarkers of brain injury were compared. Immunofluorescence and RNA sequencing with differential gene expression and pathway analysis were used to assess the integrity of the peri-lesion BBB. RESULTS: Exosome-treated animals had significantly less (p < 0.05) brain swelling and smaller lesion size. They also had significantly decreased (p < 0.05) intracranial pressures and increased cerebral perfusion pressures. Exosome-treated animals had significantly decreased (p < 0.05) albumin extravasation and significantly higher (p < 0.05) laminin, claudin-5, and zonula occludens-1 levels. Differential gene expression and pathway analysis confirmed these findings. Serum glial fibrillary acidic protein levels were also significantly lower (p<0.05) in the exosome-treated cohort at the end of the experiment. CONCLUSIONS: In a large animal model of TBI and HS, early treatment with a single dose of MSC-derived exosomes significantly attenuates brain swelling and lesion size, decreases levels of blood-based cerebral biomarkers, and improves BBB integrity. LEVEL OF EVIDENCE: Not applicable (pre-clinical study).
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