Natera-Rodriguez, D. E. | Search bioRxiv

bioRxiv2025

Coordinate-Dependent Neuroinflammation and Metabolic Disruption Following Experimental Traumatic Brain Injury

Traumatic brain injury (TBI) is a leading cause of long-term neurological dysfunction, with secondary neuroinflammation playing a pivotal role in disease progression. Microglia, the brains resident immune cells, respond to injury in a spectrum of activation states, influencing neuronal survival and cognitive recovery. While past studies have broadly examined neuroinflammatory responses following TBI, the influence of injury approach--specifically, anterior vs. posterior impact--on microglial activation and neuronal damage remains unexplored. This study investigated how the site of controlled cortical impact (CCI) in a moderate TBI model alters neuroinflammatory responses and neuronal vulnerability, providing key insights into coordinate-specific mechanisms of injury.

neuroscience↗

bioRxiv2025

Exosomes derived from highly scalable and regenerative human progenitor cells promote functional improvement in a rat model of ischemic stroke

Globally, there are 15 million stroke patients each year who have significant neurological deficits. Today, there are no treatments that directly address these deficits. With demographics shifting to an older population, the problem is worsening. Therefore, it is crucial to develop feasible therapeutic treatments for stroke. In this study, we tested exosomes derived from embryonic endothelial progenitor cells (eEPC) to assess their therapeutic efficacy in a rat model of ischemic stroke. Importantly, we have developed purification methods aimed at producing robust and scalable exosomes suitable for manufacturing clinical grade therapeutic exosomes. We characterized exosome cargos including RNA-seq, miRNAs targets, and proteomic mass spectrometry analysis, and we found that eEPC-exosomes were enhanced with angiogenic miRNAs (i.e., miR-126), anti-inflammatory miRNA (i.e., miR-146), and anti-apoptotic miRNAs (i.e., miR-21). The angiogenic activity of diverse eEPC-exosomes sourced from a panel of eEPC production lines was assessed in vitro by live-cell vascular tube formation and scratch wound assays, showing that several eEPC-exosomes promoted the proliferation, tube formation, and migration in endothelial cells. We further applied the exosomes systemically in a rat middle cerebral artery occlusion (MCAO) model of stroke and tested for neurological recovery (mNSS) after injury in ischemic animals. The mNSS scores revealed that recovery of sensorimotor functioning in ischemic MCAO rats increased significantly after intravenous administration of eEPC-exosomes and outpaced recovery obtained through treatment with umbilical cord stem cells. Finally, we investigated the potential mechanism of eEPC-exosomes in mitigating ischemic stroke injury and inflammation by the expression of neuronal, endothelial, and inflammatory markers. Taken together, these data support the finding that eEPCs provide a valuable source of exosomes for developing scalable therapeutic products and therapies for stroke and other ischemic diseases.

neuroscience↗