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Objective: To systematically evaluate the efficacy and safety of mesenchymal stem cell (MSC) therapy for patients with Multiple System Atrophy (MSA) by synthesising available clinical trial evidence and clarifying signals of disease modification. Background: MSA is a rapidly progressive and fatal neurodegenerative disorder for which no disease-modifying therapies exist. MSC therapy has emerged as a potential treatment, with mechanisms centered on neuroprotection and clinical benefit through anti-inflammatory and trophic effects rather than direct cell replacement. Methods: We systematically searched PubMed, Scopus, the Cochrane Library, and Web of Science for studies on mesenchymal stem cell (MSC) therapy in adults with probable or confirmed multiple system atrophy (MSA). Eligible studies included single-arm trials or comparisons with placebo or usual care. The primary outcome was safety and tolerability, assessed by the type and severity of adverse events. Secondary outcomes included the rate of disease progression measured by UMSARS total, Part I, and Part II scores. Results: A total of 123 participants from seven studies were included. MSCs were administered through multiple routes, and adverse events occurred in 65– 70% of participants but were mostly mild and transient. No serious MSC-related toxicity was reported. Several studies suggested slower disease progression following MSC therapy. For example, in Singer et al (2019), patients receiving high-dose MSCs showed a markedly lower rate of UMSARS total score progression compared with a matched historical control group (0.40 ± 0.59 vs 1.44 ± 1.42 points/month, p = 0.004), suggesting a possible dose-dependent effect. However, treatment effects varied across studies depending on dose, administration route, and disease stage. Conclusion: MSC therapy shows potential for disease modification in MSA by slowing neurological deterioration. The treatment was well tolerated, supporting the need for larger, definitive trials with standardised protocols and longer follow-up to confirm clinical benefit. Plain Language Summary: Multiple System Atrophy (MSA) is a rare, rapidly worsening brain disorder that affects movement, balance, and automatic body functions, and there are currently no treatments that can slow its progression. Mesenchymal stem cell (MSC) therapy has been suggested as a possible treatment because it may protect nerve cells and reduce inflammation rather than replace damaged neurons. We reviewed all clinical trials testing MSC therapy in adults with MSA to evaluate safety and possible effectiveness. Major medical databases were searched, and studies reporting side effects and changes in disease severity over time using a standard clinical rating scale were included. Seven studies with 123 patients were included. MSCs were given through different routes, including blood vessels, spinal fluid, or near the brain. Most patients experienced mild, short-term side effects, such as fever or headache, and no serious treatment-related problems were reported. Across studies, patients receiving MSC therapy showed slower worsening of symptoms than expected, particularly in earlier stages of MSA. While these findings are encouraging, the included studies were small and varied in design, which limits the strength of the conclusions. Larger, well-designed clinical trials are needed to determine whether MSC therapy can provide sustained clinical benefits for patients with MSA. Keywords: cerebellar dysfunction, immunomodulation, mesenchymal stem cells, multiple system atrophy, neurodegeneration, neuroprotection, Parkinsonism