Early single-dose treatment with exosomes provides neuroprotection and improves blood-brain barrier integrity in swine model of traumatic brain injury and hemorrhagic shock

Abstract

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; 5 mL) or LR + exosomes (1 × 1012 exosome particles in 5 mL LR). Animals then underwent additional shock (1 hour) followed by normal saline resuscitation. After 6 hours of observation, brain swelling (% increase compared with the uninjured side) and lesion size (mm3) 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 perilesion 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. CONCLUSION 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.

Exosomes Secreted From Bone Marrow Mesenchymal Stem Cells Attenuate Oxygen-Glucose Deprivation/Reoxygenation-Induced Pyroptosis in PC12 Cells by Promoting AMPK-Dependent Autophagic Flux

“…As an important component of paracrine signaling in stem cells, exosomes appear to be promising candidates for repairing tissue injury in place of stem cells (Lazar et al, 2018 ; Williams et al, 2020 ). Previous studies have found that BMSC-Exos can promote nerve function and improve the nervous system in ischemic stroke (Deng et al, 2019 ; Xiao et al, 2019 ; Hou et al, 2020 ; Safakheil and Safakheil, 2020 ), but the specific mechanism remains to be explored.…”

FGF20 Protected Against BBB Disruption After Traumatic Brain Injury by Upregulating Junction Protein Expression and Inhibiting the Inflammatory Response

“…TJ protein expression in brain ECs at a relatively high level, can maintain the integrity of the BBB ( Zhang et al, 2020 ), which is crucial for brain homeostasis. In contrast, disruption of BBB integrity correlates with reduced expression of TJ proteins such as Occludin, Claudin-5, and ZO ( Nag et al, 2007 ; Williams et al, 2020 ). Mechanical stress associated with acute-stage TBI not only is detrimental to cells in the nervous system but also results in injury to the microvasculature in the brain, which consists of ECs, finally increasing paracellular permeability and causing a cascade of secondary damage to brain tissue ( Alvarez et al, 2011 ).…”

Recent Advances on Extracellular Vesicles in Central Nervous System Diseases

“…In a Yorkshire swine model subjected to TBI and hemorrhagic shock, early single-dose administration (after one hour of shock) of MSC-exosomes contributed to relieving brain swelling, reducing lesion size, and maintaining BBB integrity. 131 Except for the early effects (6-hours), impact on late survival (7-days) was also observed -that is neurologic severity scores decrease significantly, accompanied by favorable neurologic recovery. 132…”