Human Schwann cell exosome treatment attenuates secondary injury mechanisms, histopathological consequences, and behavioral deficits after traumatic brain injury
Meghan O. Blaya, Yelena Pressman, MaryLourdes Andreu, William J. Moreno, Juliana Sanchez‐Molano, Nadine Kerr, Oliver Umland, Aisha Khan, Helen M. Bramlett, W Dalton Dietrich
Abstract
Traumatic brain injury (TBI) triggers a series of pathophysiological events, contributing significantly to secondary injury and long-term functional deficits. While exosome therapy is beginning to emerge as a promising avenue for various injuries, its efficacy in TBI, using preclinical models that mimic the biomechanics of human acceleration/deceleration TBI, remains largely unexplored. This study investigated the capacity of human Schwann cell-derived exosomes (hSC-Exo) to improve outcomes in a model of moderate fluid percussion injury (FPI). We found that jugular infusion of hSC-Exo 30 min after trauma attenuated acute proinflammatory responses in the ipsilateral cortex and hippocampus 24 h post-TBI, as demonstrated by a reduction in levels of key inflammasome components, and decreased activation of the STAT3/pSTAT3/SOCS3 pathway. Furthermore, exosome treatment mitigated subacute histopathological changes, including a significant decrease in cerebral edema and contusion volumes at 72 h post-injury. Immunohistochemical analysis revealed a decrease in microglial activation, characterized by a shift toward a more ramified morphology. Importantly, hSC-exosome therapy led to the preservation of both sensorimotor function subacutely and cognitive performance at chronic time points. Flow cytometry analysis of peripheral blood at 21 days post-TBI demonstrated a reduction in circulating neutrophils, indicating an attenuation of chronic systemic inflammation. These findings highlight the multifaceted therapeutic benefits of hSC-Exo in a clinically-relevant FPI model, targeting both acute and chronic neuroinflammatory processes to promote functional recovery. This study provides new evidence to support hSC-exosomes as a therapeutic strategy for TBI, and emphasizes the translational potential of human exosomes for treating acute and progressive neurological injury.