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 extracellular 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 neuroprotective 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.

Pre-clinical investigation of mesenchymal stromal cell-derived extracellular vesicles: a systematic review.

The therapeutic potential of naturally secreted micro- and nanoscale extracellular vesicles (EVs) makes them attractive candidates for regenerative medicine and pharmaceutical science applications. To date, the results of numerous publications have shown the practicality of using EVs to replace mesenchymal stromal cells (MSCs) or liposomes. This article presents a systematic review of pre-clinical studies conducted over the past decade of MSC-derived EVs (MSC-EVs) used in animal models of disease. The authors searched the relevant literature in the PubMed and Scopus databases (9358 articles), and 690 articles met the inclusion criteria. The eligible articles were placed in the following disease categories: autoimmune, brain, cancer, eye, gastrointestinal, heart, inflammation/transplantation, liver, musculoskeletal, pancreas, spinal cord and peripheral nervous system, respiratory system, reproductive system, skin, urinary system and vascular-related diseases. Next, the eligible articles were assessed for the rate of publication and global distribution, methodology of EV isolation and characterization, route of MSC-EV administration, length of follow-up, source of MSCs and animal species. The current review classifies and critically discusses the technical aspects of these MSC-EV animal studies and discusses potential relationships between methodological details and the effectiveness of MSC-EVs as reported by these pre-clinical studies.