Mesenchymal Stem Cell Therapies: Challenges in Clinical Translation and Adoption

Mesenchymal stem cell (MSC) therapies hold considerable regenerative promise, yet their clinical adoption remains hindered by unresolved heterogeneity in manufacturing protocols, inconsistent efficacy across disease domains, and gaps in translational evidence. We conducted a multi component systematic review and meta analysis of randomized controlled trials, preclinical animal studies, and health economic evaluations identified through a structured literature search and screened against predefined eligibility criteria. More than 200 studies were included across the review components; however, the number contributing to each analysis varied according to study design, outcome availability, and analytic eligibility. Eligible clinical studies with sufficiently comparable outcome data contributed to the meta regression and subgroup analyses, whereas preclinical and economic studies were analyzed within their respective evidence streams. Our methodology integrated meta regression analyses examining the impact of tissue source, culture conditions, passage number, and cell dose on clinical outcomes, alongside subgroup analyses of patient specific biological modifiers such as age, sex, and comorbidities. The results demonstrate that manufacturing variability explains a significant portion of between study heterogeneity in standardized mean differences for instance, adipose derived MSCs yielded more consistent functional benefits in knee osteoarthritis than bone marrow derived cells, and a dose threshold of at least fifty million cells was associated with superior outcomes. Long term safety data from regulated trials, including five year follow up studies, showed no major adverse signals, whereas unregulated clinic risks remained poorly quantified. The preclinical to clinical translation gap was particularly pronounced in neurological diseases, where large animal effect sizes contrasted with negligible human benefits, largely due to model mismatch and inadequate comorbidity modeling. Economic evaluation further revealed that MSC therapy for knee osteoarthritis faces uncertain cost effectiveness, as inconsistent cartilage repair and unclear durability weaken quality adjusted life year gains at current prices. The principal contribution of this work is a comprehensive framework identifying critical, actionable barriers namely, the need for standardized potency assays, validated predictive biomarkers, and improved preclinical models that must be addressed to advance MSC therapies from experimental settings into routine clinical practice.