Early Treatment with Exosomes following Traumatic Brain Injury and Hemorrhagic Shock in a Swine Model Promotes Transcriptional Changes associated with Neuroprotection

Aaron M Williams, Gerald A Higgins, Umar F Bhatti, Ben E Biesterveld, Simone E Dekker, Ranganath G Kathawate, Yuzi Tian, Zhenyu Wu, Michael T Kemp, Glenn K Wakam, Baoling Liu, Yongqing Li, Benjamin Buller, Hasan B Alam
Journal of Trauma and Acute Care Surgery 2020 June 3

BACKGROUND: We have shown that administration of mesenchymal stem cell (MSC)-derived exosomes (single dose given within 1 hour) in models of traumatic brain injury (TBI) and hemorrhagic shock (HS) is neuroprotective. The precise mechanisms responsible for the neuroprotection are not fully understood. This study was designed to investigate the transcriptomic changes in the brain that are associated with this treatment strategy.

METHODS: Yorkshire swine (40-45 kg) 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 exosomes suspended in LR (LR+EXO; 1 × 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. Peri-injured brain tissue was processed for RNA sequencing, analyzed with high through-put RNA-seq data analysis, and results compared between control and experimental groups.

RESULTS: Exosome treatment significantly increased (p < 0.005) gene expression associated with neurogenesis, neuronal development, synaptogenesis, and neuroplasticity. It also significantly reduced (p < 0.005) genes associated with stroke, neuroinflammation, neuroepithelial cell proliferation and non-neuronal cell proliferation contributing to reactive gliosis. Exosomes treatment also significantly increased (p < 0.005) the genes that are associated with the stability of blood-brain barrier.

CONCLUSIONS: Administration of a single dose of exosomes induces transcriptomic changes suggestive of neuroprotection. Their use as a treatment of TBI is promising, and requires further investigation for human translation.

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

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