Early Single-Dose Exosome Treatment Improves Neurologic Outcomes in a 7-Day Swine Model of Traumatic Brain Injury and Hemorrhagic Shock.

BACKGROUND: Early single-dose treatment with human mesenchymal stem cell (MSC)-derived exosomes promotes neuroprotection and promotes blood-brain barrier (BBB) integrity in models of traumatic brain injury (TBI) and hemorrhagic shock (HS) in swine. The impact of an early single dose of exosomes on late survival (7-day), however, remains unknown. We sought to evaluate the impact of early single-dose exosome treatment on neurologic outcomes, brain lesion size, inflammatory cytokines, apoptotic markers, and mediators of neural plasticity in a 7-day survival model.

METHODS: Yorkshire swine were subjected to a severe TBI (8-mm cortical impact) and HS (40% estimated total blood volume). After one hour of shock, animals were randomized (n=4/cohort) to receive either lactated Ringer's (LR; 5mL) or LR + exosomes (LR+EXO; 1 × 10 exosome particles). After an additional hour of shock, animals were resuscitated with normal saline. Daily neurologic severity scores (NSS) were compared. At 7 days following injury, lesion size, inflammatory markers, and mediators of inflammation (NF-κB), apoptosis (BAX), and neural plasticity (BDNF) in brain tissue were compared between groups.

RESULTS: Exosome-treated animals had significantly lower NSS (first 4 days; p < 0.05) and faster neurologic recovery. At 7-days, exosome-treated animals had significantly smaller (p < 0.05) brain lesion sizes. Exosome-treated animals also had significantly lower levels of inflammatory markers (IL-1, IL-6, IL-8, and IL-18) and higher granulocyte-macrophage colony stimulating factor (GM-CSF) levels compared to the control animals, indicating specific impacts on various cytokines. BAX and NF-κB levels were significantly lower (p < 0.05) in exosome-treated animals, while BDNF levels were significantly higher (p < 0.05) in the exosome-treated animals.

CONCLUSIONS: In a large animal model of TBI and HS, early single-dose exosome treatment attenuates neurologic injury, decreases brain lesion size, inhibits inflammation and apoptosis, and promotes neural plasticity over a seven-day period.

LEVEL OF EVIDENCE: Not applicable (pre-clinical study).