Neuro-Behavioral Improvement and Mechanistic Pathways of Bone Marrow-Derived Mesenchymal Stem Cells and Exosomes in Experimental Multiple Sclerosis: A Systematic Review and Meta-analysis

Multiple sclerosis (MS) is a chronic inflammatory and neurodegenerative disorder with limited disease-modifying treatments. Bone marrow-derived mesenchymal stem cells (BM-MSCs) and their exosomes have emerged as promising therapeutic candidates due to their immunomodulatory and neuroprotective properties. This systematic review and meta-analysis evaluated the efficacy of BM-MSC and MSC-derived exosome therapy on clinical outcomes and mechanistic pathways in experimental autoimmune encephalomyelitis (EAE) models. A comprehensive search was conducted across PubMed, Web of Science, Scopus, Embase, ProQuest, and gray literature sources. In vivo studies investigating BM-MSC or MSC-exosome interventions in EAE models were included. Clinical score data were synthesized using random-effects models with standardized mean differences (SMD). Mechanistic outcomes included demyelination, GFAP and IBA1 expression, and inflammatory cytokines. Study quality was assessed using SYRCLE’s risk of bias tool, and publication bias was evaluated through funnel plots, Egger’s test, and trim-and-fill analysis. Sixty-one studies met inclusion criteria, with 48 included in the meta-analysis. BM-MSC treatment significantly improved clinical scores (SMD = –1.49, 95% CI: –1.86 to –1.11, I² = 84.31%, P = 0.00) and reduced demyelination (SMD = –2.96, 95% CI: –4.49 to –1.43, I² = 95.78%, P = 0.00). MSC therapy significantly decreased GFAP-positive astrocytes (SMD = –2.99, P = 0.03) and IBA1-positive microglia (SMD = –.82, P = 0.00). Furthermore, MSC treatment led to a significant reduction in TNF-α levels (SMD = –8.58, 95% CI: –6.23 to –0.92, P = 0.03). In contrast, effects on IL-10, IL-17, and IFN-γ levels were not statistically significant. MSC-derived exosomes showed a non-significant reduction in clinical scores (SMD = –3.14, 95% CI: –6.71 to 0.42, I² = 97.43%, P = 0.08). BM-MSC therapy demonstrates significant benefits in EAE models through immunomodulation and neuroprotection. While MSC-derived exosomes show potential, their effects require further validation. Future research should focus on standardized protocols, optimal dosing strategies, and mechanistic studies to facilitate clinical translation.