BMSC exosomes promote neurogenesis and alleviate behavioral deficits in chronic traumatic encephalopathy: an animal model-based study.

Chronic traumatic encephalopathy (CTE), a progressive neurodegenerative disorder, poses a significant threat to human health. The lack of validated animal models has impeded mechanistic studies and the development of treatments for CTE. Recent evidence suggests that bone marrow mesenchymal stem cell-derived exosomes (BMSC-exos) represent a promising strategy for treating central nervous system injuries; however, their efficacy and mechanisms of action in CTE remain unexplored. In this study, we developed and optimized a CTE mouse model that recapitulates the core clinical features observed in CTE patients, including the delayed symptom onset. Using this model, we investigated the therapeutic effects of BMSC-exos. Our results indicate that BMSC-exos ameliorated anxiety-like behaviors and cognitive deficits in CTE mice, restoring them to levels comparable to those in noninjured control mice. Mechanistically, analysis of the hippocampal subgranular zone (SGZ) revealed that BMSC-exos restored the chronic CTE-induced reduction in the number of doublecortin (DCX)-positive immature neurons without altering the population of Sox2-Nestin-double-positive neural stem cells, indicating a primary effect on promoting neuronal differentiation efficiency or immature neuron survival rather than stem cell proliferation. Furthermore, BMSC-exos preserved neuronal structural integrity during late-stage CTE, indicating a critical role in maintaining synaptic plasticity and dendritic complexity. Collectively, our study provides promising evidence for the therapeutic potential of BMSC-exos in CTE, offering new insights for future CTE therapeutics.