Early Single-Dose Exosome Treatment Improves Neurologic Outcomes in a 7-Day Swine Model of Traumatic Brain Injury and Hemorrhagic Shock
Williams AM, Wu Z, Bhatti UF, Biesterveld BE, Kemp MT, Wakam GK, Vercruysse CA, Chtraklin K, Siddiqui AZ, Pickell Z, Dekker SE, Tian Y, Liu B, Li Y, Buller B, and Alam HB. Early Single-Dose Exosome Treatment Improves Neurologic Outcomes in a 7-Day Swine Model of Traumatic Brain Injury and Hemorrhagic Shock. J Trauma Acute Care Surg 2020.
J Trauma Acute Care Surg
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).
ePub ahead of print