Mesenchymal Stem Cell-Derived Exosomes Provide Neuroprotection and Improve Long-Term Neurologic Outcomes in a Swine Model of Traumatic Brain Injury and Hemorrhagic Shock

Abstract

Combined traumatic brain injury (TBI) and hemorrhagic shock (HS) remains a leading cause of preventable death worldwide. Mesenchymal stem cell-derived exosomes have demonstrated promise in small animal models of neurologic injury. To investigate the effects of exosome treatment in a clinically realistic large animal model, Yorkshire swine underwent TBI and HS. Animals were maintained in shock for 2 h before resuscitation with normal saline (NS). Animals were then resuscitated either with NS (3 × volume of shed blood) or with the same volume of NS with delayed exosome administration (1 × 10 particles/4 mL) (n = 5/cohort). Exosomes were administered 9 h post-injury, and on post-injury days (PID) 1, 5, 9, and 13. Neurologic severity scores (NSS) were assessed for 30 days, and neurocognitive functions were objectively measured. Exosome-treated animals had significantly lower NSS (p < 0.05) during the first five days of recovery. Exosome-treated animals also had a significantly shorter time to complete neurologic recovery (NSS = 0) compared with animals given NS alone (days to recovery: NS = 16.8 ± 10.6; NS + exosomes = 5.6 ± 2.8; p = 0.03). Animals treated with exosomes initiated neurocognitive testing earlier (days to initiation: NS = 9.6 ± 0.5 vs. NS + exosomes = 4.2 ± 0.8; p = 0.008); however, no difference was seen in time to mastery of tasks. In conclusion, treatment with exosomes attenuates the severity of neurologic injury and allows for faster neurologic recovery in a clinically realistic large animal model of TBI and HS.

Potential of mesenchymal stem cells alone, or in combination, to treat traumatic brain injury

“…Later studies are consistent with these results . MSC‐derived exosomes have also been tested in porcine model of TBI coupled with hemorrhagic shock; consistent with the rodent data, the pigs had fewer cognitive deficits as determined with a neurological severity score and recovered faster than nontreated pigs . There is also evidence for MSC inducing immune suppression and anti‐inflammation; stimulating neurogenesis and angiogenesis; activating survival pathways and inhibiting apoptotic pathways; and enhancing neuroplasticity through neurite outgrowth and synaptogenesis …”

“…It is imperative that larger animal models are used for the testing of new therapies including cell therapies so that we can distinguish good candidate therapies that are likely to succeed in clinical trials from those that will not. There has been some work in the development and characterization of porcine and ovine models of TBI, but there are currently no studies of MSC therapies and only a handful of MSC‐derive exosome studies in these larger animal models TBI models …”

Cell-to-Cell Communication in Learning and Memory: From Neuro- and Glio-Transmission to Information Exchange Mediated by Extracellular Vesicles

“…In the brain, MSCs provide a suitable environment for axonal growth and neurogenesis, thus ameliorating neurological deficits [257]. Now, MSCs are also very active producers of EVs, and these EVs seem to share with intact MSCs the ability to counteract degenerative diseases and cognition deficits while promoting axonal growth, learning, and memory [299,300]. Moreover, they do not replicate and cannot undergo uncontrolled division after implantation.…”

Engineering Extracellular Vesicles as Nanotherapeutics for Regenerative Medicine

“…Due to their paracrine mechanism of action, EVs have seen great success as injectable therapeutics for neuroprotection, cardioprotection and renoprotection. In a swine model of traumatic brain injury and hemorrhagic shock, animals that received bone marrow MSC-derived EVs via intravenous injection showed significantly lower neurologic impairment and had a faster full neurological recovery to baseline functions [47]. Similarly, intravenous administration of EVs from human embryonic stem cell-derived neural stem cells improved the functional and physical outcomes after thromboembolic stroke in middle-aged mice [48].…”