Introduction:Endothelial dysfunction underlies the pathophysiology of cardiovascular disease (CVD) in patients with diabetes mellitus (DM), but no known effective therapies exist. The randomized, double-blind ACESO clinical trial evaluated the safety and efficacy of allogeneic human mesenchymal stem cells (allo-MSCs) infusion to target endothelial dysfunction in Type 2 DM subjects.Methods:An open label pilot phase (n=6) was followed by a blinded, randomized phase (n=10) study. DM subjects with endothelial dysfunction received a single peripheral intravenous infusion of either 20 or 100 million allo-MSCs (obtained from 3 healthy bone marrow donors) and followed for 1 yr. The primary endpoint was incidence of treatment-emergent serious adverse events (TE-SAE) within 1-month post-infusion. Secondary endpoints assessed endothelial function via endothelial progenitor cell-colony forming units (EPC-CFUs) and flow-mediated dilation (FMD%).Results:Participants had well-controlled DM, blood pressure, and kidney function (GFR ≥50 ml/min), and most were taking statins. The 6 pilot-phase participants were men (1 Asian, 5 non-Hispanic white) with mean (±SD) age of 69.3 (9.6) years. The 10 randomized participants were 5 men and 5 women (5 Hispanic, 3 non-Hispanic Black), with mean age of 60.9 (10.6) years. No TE-SAEs were reported. None of the patients in the pilot phase developed Panel Reactive Antibodies (PRAs). One randomized subject had a moderate increase in PRAs after infusion. Both treatment groups (20 and 100M allo-MSCs) in the pilot and randomized phases showed increased EPC-CFUs over time, particularly at 14 and 28 days post-infusion, that was sustained at 6-12 months. FMD data followed a trend rising above baseline and peaking at days 7 to 14, and then subsided to pre-infusion levels by 1 yr.Conclusion:Peripheral infusion of allo-MSCs for patients with DM and endothelial dysfunction is safe. Allo-MSCs improve EPCs and FMD within 14 to 28 days post-infusion, and the effect is sustained for 6 to 12 months. Larger clinical trials are warranted to assess the efficacy of allo-MSC therapy for cardiovascular outcomes in diabetic patients.Clinical Trial Registration:URL: https://www.clinicaltrials.gov.; Unique ID: NCT02886884