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ObjectiveTo synthesize human clinical evidence from systematic reviews and meta-analyses on stem cell-based therapies for ischemic stroke, with an emphasis on mesenchymal stem cell-based interventions, and to appraise their efficacy, safety, methodological quality, overlap, and certainty of evidence.MethodsThis Open Science Framework-registered umbrella review followed Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2020 and Joanna Briggs Institute guidance. PubMed/MEDLINE, Scopus, and Web of Science were searched through 1 November 2025. Eligible studies were systematic reviews or meta-analyses of randomized or nonrandomized human clinical studies evaluating mesenchymal stem cells or related stem cell-based interventions for ischemic stroke. Two reviewers independently performed study selection, data extraction, AMSTAR 2 (A MeaSurement Tool to Assess systematic Reviews 2) appraisal, and GRADE (Grading of Recommendations Assessment, Development and Evaluation)-based certainty assessment. Because of overlap among reviews and heterogeneity in cell products, administration routes, timing, and outcomes, the findings were synthesized narratively rather than through a de novo meta-analysis.ResultsTwenty-six reviews were included. The evidence suggested possible improvements in neurological impairment, disability, activities of daily living, and motor recovery; however, effect estimates varied according to cell type, administration route, timing after stroke, and follow-up duration. Intravenous administration was the most frequently studied and appeared feasible, with acceptable short-term safety reporting, whereas intra-arterial and intracerebral routes showed greater procedure-related concerns. Short-term adverse events were not consistently increased. However, the evidence remains insufficient regarding rare or delayed risks, including tumorigenesis, ectopic tissue formation, embolic events, and alloimmunogenicity. The certainty of evidence was low to moderate for most efficacy outcomes, moderate for short-term adverse events, and very low to low for long-term or rare safety outcomes.ConclusionsStem cell-based therapies, particularly mesenchymal stem cell-based approaches, may improve selected neurological and functional outcomes after ischemic stroke. However, overlapping reviews, heterogeneous interventions, small early-phase trials, and limited long-term follow-up require cautious interpretation. Adequately powered, standardized, multicenter trials with long-term safety surveillance are needed before routine clinical implementation.