Immuno-Modulation and neuroprotection mediate the therapeutic effect of exosomes in mice model of autism

Abstract

Background & Aim Background: During the recent decade, exosomes that derived from mesenchymal stem cells (MSC-exo) have been spotlighted as a promising therapeutic target for various clinical indications, including neurological disorders. We have previously shown that intranasal administration of MSC-exo, cross the BBB and significantly ameliorate autistic like behavioral phenotype in BTBR and SHANK3 animal models of autism, representing a potential therapeutic strategy to reduce symptoms of autism spectrum disorder (ASD). Objective: In order to study the mechanism of action and the cellular pathways in which the adipose-derived MSC-exo activate their target, we preformed RNA sequencing analysis of primary neurons isolated from SHANK3 mice treated with MSC-exo. Methods, Results & Conclusion Methods: Primary neuronal cell cultures were prepared from newborn SHANK3 homozygotes mice model of autism. Cultures were treated with 40ul MSC-exo (107 particles/ul), isolated from human adipocytes, followed by RNA sequencing. The alterations in gene expression between the treated and intact neurons were analyzed for gene ontology and pathways and were also compared to proteomics analysis of the MSC-exo in order to find regulatory proteins that may lead to these differences. Results: Bioinformatic analysis revealed several up-regulators proteins that might be responsible for the increase in anti-inflammatory and protective factors seen in the mice neurons treated with MSC-exo. One of them is BDNF which is known as an essential growth factor responsible for neuroprotection and neurogenesis. Importantly, no difference in the genetic expression of cancer-related genes were identified following MSC-exo treatment indicating for their safety. Conclusions: Our data suggest that adipose-derived MSC-exo carry therapeutic potential in ASD via alternation in gene-expression related mainly to immuno-modulation, reduce neuro-inflammation and increase neuroprotection and neurogenesis. The beneficial effects of the MSC-exo treatment in mice models is being translated to a novel, easy to administer, therapeutic strategy to reduce the symptoms of ASD.