Direct infusion of bone marrow-derived progenitor cells delays atherosclerotic plaque progression and decreases inflammatory mediators in a murine model of atherosclerosis

Abstract

Purpose: The effects of direct infusion or indirect mobilization of progenitor cells on atherosclerotic plaque progression are not clear. We sought to investigate the effects of lin-/sca+ cells, endothelial progenitor cells (EPCs) and granulocyte colony-stimulating factor (G-CSF) administration on atherosclerotic plaque progression. Methods: Apolipoprotein E-deficient (apoE-/-) mice were splenectomized and treated with high-cholesterol diet for 6 weeks in order to induce atherosclerotic plaque development. Bone marrow derived Lin-/sca-1+ cells were isolated and further cultured to early growth endothelial progenitor cells (EPCs). Mice were divided in four groups (n=10/group) and received two intravenous injections of 5x105 cells (lin-/sca-1+ or EPCs), or granulocyte colony-stimulating factor (G-CSF 100mcg/kg/day) for 7 days or normal saline. The same interventions were administered to animals, which had undergone unilateral hind-limb ischemia. Effects on inflammatory parameters, lesion severity, and atherosclerotic plaque area size were assessed. Results: The administration of both G-CSF and progenitor cells significantly decreased the levels of IL-6, 6 weeks after the initiation of treatment. The effect of treatment on pro-inflammatory molecules 7 days post-treatment was not significant. Atherosclerotic lesion area was reduced by G-CSF (atherosclerotic plaque area percentage 22.94%±3.68, p=0.001), by lin-/sca-1+ (23.27%±5.98, P=0.002) and cultured EPCs (23.16±4.86%, p=0.002) compared to control (32.75%±7.05). The percentage of severe lesions was higher in the control group compared to treatment groups [(80% in controls vs 50% in the G-CSF group (p< 0.05), 46% in the lin-/sca-1+ group (p< 0.05) and 56% in the EPC group (p<0.05)]. In the atherosclerotic mice that underwent limb ischemia, the atherosclerotic plaque area degree was not significantly different between the treatment groups [(G-CSF (26.86%±4.84, P=0.105), lin-/sca-1+ (29.15%±5.42, P=0.188), cultured EPCs-treated mice (28.07±5.89%, P=0.202)] and the control (31%±7.39). Conclusions: Direct infusion of progenitor cells and indirect mobilization of hematopoietic progenitor cells decreased plaque progression and levels of inflammatory molecules in a murine model of atherosclerosis. Treatment with G-CSF, lin-/sca-1+, or EPCs may exert beneficial effects on vascular inflammation and atherosclerotic plaque progression. However, the effects are diminished in an ischemic setting.