Stem Cell Derived Extracellular Vesicle Therapy for Multiple Sclerosis, A Systematic Review and Meta-Analysis of Preclinical Studies.

Stem cell therapy holds promise for multiple sclerosis (MS), with efficacy of different stem cell types reported across a range of preclinical MS animal models. While stem cell therapy has been approved for a small number of diseases in humans, extracellular vesicles (EVs) may provide an efficacious, cost-effective, and safer alternative to stem cell therapy. To this end, we conducted a systematic review with meta-analysis to assess the effectiveness of stem cell-derived secretome (EV and conditioned media (CM)) in animal models of MS. The data were extracted to calculate standardized mean differences for primary outcome measure of disease severity, using a random effect model. Additionally, several subgroup analyses were conducted to assess the impact of various study variables such as stem cell type and source, stem cell modification, route and time of administration, number of animals and animal's age, and EV isolation methods on secondary outcome. Publication quality and risk of bias were assessed. Overall, 19 preclinical studies were included in the meta-analysis where stem cell EV/CM was found to significantly reduce disease severity in EV-treated (SMD = 2, 95% CI: 1.18-2.83, P < .00001) and CM-treated animals (SMD = 2.58, 95% CI: 1.34-3.83, P < .00001) compared with controls. Our analysis indicated that stem cell secretome has a positive effect on reducing demyelination, systemic neuroinflammation, and disease severity in preclinical models of MS. These findings indicate a potential therapeutic effect that merits investigation and validation in clinical settings.