Interleukin-8 receptors A and B (IL8RA and RB) on neutrophil membrane bind to IL8 and play a critical role in neutrophil recruitment to sites of injury. We developed a novel targeted cell therapy using endothelial cells (ECs) that overexpress IL8RA/B to repair the cardiovascular injury. Rat aortic ECs (RAECs), induced-pluripotent stem ECs (rat-iPS-ECs), or porcine coronary artery ECs (PCAECs) were transduced with adenoviruses carry IL8RA/B genes. We hypothesized that i.v. transfusion of ECs overexpressing IL8RA/B will target to the area of injury, decrease inflammatory response, and inhibit neointima formation in balloon-injured rat carotid arteries and pig stent-injured coronary arteries.Design and Method:
In rat study, 12 wk old male Sprague-Dawley rats received balloon injury of the carotid artery and were transfused with 1) vehicle, 2) 1.5x106 RAECs or rat-iPS-ECs, or 3) 1.5x106 IL8RA/B-RAECs or rat-iPS-IL8RA/B-ECs immediately after the vascular injury. One group of rats was sacrificed 24 hr post injury to measure infiltration of neutrophils and levels of inflammatory cytokines. A second group was sacrificed 2 wks post injury to measure the neointima formation. In pig study, young Yorkshire pigs received stent implantation in the LAD and circumflex coronary arteries and were transfused with vehicle or 15x106 IL8RA/B-PCAECs. Pigs were sacrificed 4 wks after stenting for measurement of restenosis.Results:
In the rat model, transfusion with IL8RA/B-RAECs or rat-iPS-IL8RA/B-ECs significantly decreased neutrophils infiltration, inflammatory cytokines expression and neointima formation in the injured carotid artery. Similarly, in the pig model, administration of IL8RA/B-PCAECs reduced the stenting-induced coronary arterial restenosis.Conclusions:
Transfused adult ECs or iPS-ECs with overexpression of IL8RA and RB mimic the behavior of neutrophils that target to injured blood vessels, preventing inflammation and neointima formation. Targeted delivery of ECs to arteries with endoluminal injury provides a novel strategy for the prevention and treatment of cardiovascular disease.