Distinct roles of extracellular vesicles derived from various mesenchymal stem cell sources in bone regeneration: a systematic review and meta-analysis.

Abstract

<h4>Purpose</h4>This systematic review and meta-analysis evaluated the therapeutic efficacy and underlying mechanisms of mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) in bone regeneration, with subgroup analyses based on EV source, dose, and delivery route.<h4>Methods</h4>A comprehensive search of PubMed, Embase, and Web of Science (2015-2024) identified 2,414 records, of which 20 in vivo randomized controlled trials (RCTs) met the inclusion criteria. Data on animal models, EV sources, dosing, administration methods, and outcomes - including bone volume/total volume, histology, biomechanics - were extracted. Meta-analyses and subgroup comparisons were conducted using random-effects models.<h4>Results</h4>MSC-EVs significantly promoted bone regeneration (pooled standardized mean difference [SMD]=2.17; 95% confidence interval: 2.08-2.25; P<0.00001). Local administration (n=15) and high-dose regimens (≥1×10¹⁰ particles/kg; n=16) were both effective (SMD=2.16 and 2.11, respectively). Subgroup analyses revealed consistent efficacy across EV sources. Rat models (n=13) yielded an SMD of 2.8, and RCTs (n=12) showed low heterogeneity (I²=25%) with an SMD of 2.9. Bone marrow-drived MSC-EVs (BMSC-EVs) exhibited superior osteogenic potential in critical-size defects; umbilical cord-drived MSC-EVs (UCMSC-EVs) showed anti-inflammatory and osteoprotective properties; and human-induced pluripotent stem cell-derived MSC-EVs (hiPS-MSC-EVs) supported multifunctional tissue repair. Sensitivity analyses confirmed result stability.<h4>Conclusion</h4>MSC-EVs significantly enhance bone regeneration in a source-dependent manner: BMSC-EVs demonstrate superior efficacy in critical-size defects; UCMSC-EVs are effective in inflammatory osteolysis; hiPS-MSC-EVs support multifunctional tissue repair. Optimizing dosing (≥1×10¹⁰ particles/kg) and delivery strategies is essential for successful clinical translation.