Clonal mesenchymal stem cell-derived extracellular vesicles improve mouse model of weight drop-induced traumatic brain injury through reducing cistauosis and apoptosis

Objective: Traumatic brain injury (TBI) is a major risk factor for disabilities globally with no effective treatment thus far. Recently, homogenous population of clonal mesenchymal stem cells (cMSC) and their derived extra-cellular vesicles (cMSC-EVs) have been proposed as a promising TBI treatment strategy. We herein investigated possible therapeutic effect of cMSC-EVs in TBI treatment and the underlying mechanisms considering cis p-tau as an early hallmark of TBI.Methods: We examined the EVs morphology, size distribution, marker expression, and uptake. Moreover, the EVs neuroprotective effects were studied in both in-vitro and in-vivo model. We also examined the anti-cis p-tau antibody-loading characteristics of the EVs. We treated TBI mouse model with EVs; prepared from cMSC-conditioned media. TBI mice were given cMSC-EVs intravenously and their cognitive functions were analyzed two months of the treatment. We employed immunoblot analysis to study the underlying molecular mechanisms.Results: We observed a profound cMSC-EVs uptake by primary cultured neurons. We found a remarkable neu-roprotective effect of cMSC-EVs upon nutritional deprivation stress. Furthermore, cMSC-EVs were effectively loaded with an anti-cis p-tau antibody. There was a significant improvement in cognitive function in TBI animal models treated with cMSC-EVs compared to the saline-treated group. There was a decreased cis p-tau and cleaved caspase3 as well as increased p-PI3K in all treated animals.Conclusions: The results revealed that cMSC-EVs efficiently improved animal behaviors after TBI by reducing cistauosis and apoptosis. Moreover, the EVs can be employed as an effective strategy for antibody delivery during passive immunotherapy.

Automated summary

This study investigated the therapeutic effects of clonal mesenchymal stem cell-derived extracellular vesicles (cMSC-EVs) in traumatic brain injury (TBI) treatment. The results showed that cMSC-EVs efficiently improved cognitive function in TBI animal models, reduced cis p-tau and cleaved caspase3 protein expression, and increased p-PI3K expression. Moreover, cMSC-EVs were able to effectively load an anti-cis p-tau antibody, suggesting their potential use in antibody delivery for passive immunotherapy.