Cultured Human Bone Marrow–Derived CD31+ Cells Are Effective for Cardiac and Vascular Repair Through Enhanced Angiogenic, Adhesion, and Anti-Inflammatory Effects

BACKGROUND: Cell therapy for cardiovascular disease has been limited by low engraftment of administered cells and modest therapeutic effects. Bone marrow (BM) -derived CD31(+) cells are a promising cell source owing to their high angiovasculogenic and paracrine activities. OBJECTIVES: This study sought to identify culture conditions that could augment the cell adhesion, angiogenic, and anti-inflammatory activities of BM-derived CD31(+) cells, and to determine whether these cultured CD31(+) cells are effective for cardiac and vascular repair. METHODS: CD31(+) cells were isolated from human BM by magnetic-activated cell sorting and cultured for 10 days under hematopoietic stem cell, mesenchymal stem cell, or endothelial cell culture conditions. These cells were characterized by adhesion, angiogenesis, and inflammatory assays. The best of the cultured cells were implanted into myocardial infarction (MI) and hindlimb ischemia (HLI) models to determine therapeutic effects and underlying mechanisms. RESULTS: The CD31(+) cells cultured in endothelial cell medium (EC-CD31(+) cells) showed the highest adhesion and angiogenic activities and lowest inflammatory properties in vitro compared with uncultured or other cultured CD31(+) cells. When implanted into mouse MI or HLI models, EC-CD31(+) cells improved cardiac function and repaired limb ischemia to a greater extent than uncultured CD31(+) cells. Histologically, injected EC-CD31(+) cells exhibited higher retention, neovascularization, and cardiomyocyte proliferation. Importantly, cell retention and endothelial transdifferentiation was sustained up to 1 year. CONCLUSIONS: Short-term cultured EC-CD31(+) cells have higher cell engraftment, vessel-formation, cardiomyocyte proliferation, and anti-inflammatory potential, are highly effective for both cardiac and peripheral vascular repair, and enhance survival of mice with heart failure. These cultured CD31(+) cells may be a promising source for treating ischemic cardiovascular diseases.