Mesenchymal Stem Cell Therapies for ARDS: A Systematic Review of Efficacy and Safety

Introduction: Acute respiratory distress syndrome (ARDS) is a prominent cause of mortality in critically ill patients. Mesenchymal stem/stromal cells (MSCs) and their extracellular vesicles (EVs) offer immunomodulatory and regenerative properties that may minimize lung injury. This review conducts a systematic evaluation of randomized controlled trials (RCTs) that compare MSC/EV therapy with standard therapy for ARDS.


Methods: We comprehensively searched PubMed and Scopus for eligible RCTs up to July 2025 that involved adult patients with either COVID-19-related or non-COVID ARDS and received MSCs or MSC-derived EVs as an intervention alongside a placebo or standard-care comparator. Only prospective RCTs were included, and studies that did not report clinical outcomes such as mortality, ventilator-free days (VFDs), PaO₂/FiO₂ ratios, or biomarkers of inflammation were excluded. Ultimately, 16 trials met our criteria.


Results: All 16 RCTs indicated that MSC/EV therapy was well tolerated, with no increase in infusion-related adverse events. Among these 16 trials, 6 reported a mortality benefit (8% to 43% vs 20% to 80% in controls). However, 7 trials reported no mortality benefit, and 3 did not report mortality outcomes. VFDs were studied in 11 trials: 3 demonstrated significant improvement, 4 showed no difference, and 4 lacked statistical significance. Oxygenation (PaO₂/FiO₂) improved significantly in 4 of 9 reporting trials, while others found no evident change. Six studies reported notable reductions in inflammatory markers like IL-6, CRP, and TNF-α, supporting the immunomodulatory effects of MSCs and EVs. One large multicenter RCT (N=222) did not find any difference in 30-day mortality (37.5% vs. 42.7%; RR 0.88; 95% CI 0.64–1.21; P = 0.43) or 60-day VFDs (median rank 117.3 vs. 102.0). Non-COVID ARDS patients were only included in 3 trials, and none showed statistically significant clinical benefit.


Conclusions: Overall, MSC and EV therapies for ARDS exhibit a consistent safety profile, but efficacy evidence remains limited. While small early-phase trials showed promising improvements in outcomes, larger RCTs have not confirmed significant benefits. MSC-based treatments for ARDS should be considered investigational, and further high-quality trials are needed to determine any actual impact on ARDS outcomes.