Efficacy and safety of stem cell therapy for dry eye disease: a systematic review and meta-analysis

INTRODUCTION: Dry eye disease (DED) is a multifactorial ocular surface disorder characterized by loss of tear film homeostasis, inflammation, neurosensory abnormalities, and epithelial damage. Despite the availability of topical immunomodulators and procedural interventions, a substantial proportion of patients with moderate-to-severe or refractory DED experience persistent symptoms and inadequate ocular surface recovery. Stem cell-based therapies, particularly mesenchymal stem cells (MSCs) and MSC-derived exosomes, have emerged as regenerative and immunomodulatory strategies aimed at restoring epithelial integrity and tear film stability rather than providing solely symptomatic relief. We conducted a systematic review and meta-analysis to evaluate the clinical efficacy and safety of stem cell and stem cell-derived therapies in human DED. METHODS: This study followed PRISMA 2020 guidelines and was prospectively registered in PROSPERO (CRD420251057372). Six databases were searched from inception to May 14, 2025. Eligible studies were peer-reviewed human clinical investigations evaluating stem cell-based interventions for DED and reporting objective efficacy outcomes such as Schirmer test, tear break-up time (TBUT), corneal fluorescein staining (CFS), or patient-reported outcomes including the Ocular Surface Disease Index (OSDI). Pooled mean differences (MDs) or standardized mean differences (SMDs) with 95% confidence intervals (CIs) were calculated. Statistical heterogeneity was assessed using the I² statistic. Risk of bias was evaluated using RoB 2 for randomized controlled trials and ROBINS-I for non-randomized studies. RESULTS: Six studies comprising 131 patients were included. Stem cell-based therapies demonstrated significant improvements in tear production, tear film stability, epithelial integrity, and symptom burden. Schirmer test improved by MD = 4.70 mm (95% CI, 4.18-5.22; p < 0.001; I² = 12.59%), indicating a consistent enhancement of aqueous tear secretion. TBUT showed a large standardized improvement with pooled SMD = 1.125 (95% CI, 0.821-1.428; p < 0.001), although randomized trials demonstrated smaller effect sizes than non-randomized studies. OSDI scores decreased by MD = -11.44 points (95% CI, -22.71 to -0.17; p = 0.047), reflecting symptomatic improvement but with substantial between-study variability. Corneal fluorescein staining decreased by MD = -1.04 (95% CI, -1.23 to -0.84; p < 0.001; I² = 0%), supporting epithelial recovery. No serious treatment-related adverse events were reported; however, safety reporting was heterogeneous and follow-up durations were limited. CONCLUSION: Stem cell and stem cell-derived therapies are associated with significant improvements in both objective and subjective outcomes in DED and demonstrate a favorable short-term safety profile. Nevertheless, heterogeneity in cell source, delivery route, dosage, and study design limits generalizability. Larger, rigorously designed randomized trials with standardized protocols and longer follow-up are required to confirm efficacy and establish long-term safety.