Therapeutic Efficacy of Mesenchymal Stem Cells at the Level of Biomarkers in Multiple Sclerosis: A Systematic Review.

Multiple sclerosis (MS), particularly progressive forms, remains a significant therapeutic challenge. Mesenchymal stem cell (MSC) therapy offers promising immunomodulatory and neuroprotective potential. This systematic review comprehensively evaluates the therapeutic efficacy and biomarker response to MSC therapy in MS. Following PRISMA 2020 guidelines, we searched PubMed, Scopus, Web of Science, and Embase up to January 3, 2026. Seventeen publications, corresponding to 16 distinct clinical trials (five unique randomized controlled trials [RCTs] reported in six publications, and 11 non-randomized studies), were included. Data on MSC sources, dosing, routes of administration, and multi-level outcomes (clinical, imaging, immunological, and objective biomarkers) were extracted. Quality was assessed using the Joanna Briggs Institute tools. Analysis of the included RCTs revealed divergent clinical efficacy. A large trial of intravenous bone marrow-derived MSCs showed no significant improvement in the Expanded Disability Status Scale (EDSS). In contrast, trials employing intrathecal (IT) administration or umbilical cord-derived MSCs reported potential benefits in disability and functional measures (e.g., T25-FW, 9-HPT). Biomarker analysis showed high inconsistency; however, IT MSC administration in one RCT was associated with a significant reduction in cerebrospinal fluid neurofilament light chain (NfL) levels, suggesting a route-dependent neuroprotective effect. Findings on immunological markers (e.g., TNF-α, IL-17) were derived predominantly from studies with a high risk of bias. Critically, MSC therapy demonstrated an excellent safety profile across all studies, with no serious treatment-related adverse events reported. MSC therapy demonstrates an excellent safety profile in MS. Intrathecal and umbilical cord-derived approaches show tentative clinical and biomarker benefits, especially concerning neuroprotection (NfL reduction). However, definitive conclusions are constrained by significant methodological heterogeneity and short follow-up periods across trials. Future research must focus on standardized, large-scale RCTs to optimize MSC source and administration route, and urgently needs to validate the predictive accuracy of biomarkers, beyond reporting only changes in expression levels.