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K.–H. Chang, A. Afzal, M.S. Segal, J.V. Busik, M.B. Grant; Endothelial Progenitor Cells (EPC) Dysfunction in Diabetic Patients Is Due to Decreased Response to Chemokine, Stromal Derived Factor–1 (SDF–1) . Invest. Ophthalmol. Vis. Sci. 2005;46(13):402.
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© ARVO (1962-2015); The Authors (2016-present)
Purpose: Reduced endothelial progenitor cell (EPC) number and activity in diabetes mellitus (DM) may be responsible for defective endothelial repair leading to formation of acellular capillaries seen in diabetic retinopathy. SDF–1, a chemokine involved in EPC recruitment to areas of injury, facilitates the participation of EPC in the repair process. CD34 + cells are a major source of EPC. The mechanism of EPC dysfunction is not known, but is likely to involve hyperglycemia, dyslipidemia and reduced nitric oxide levels (NO) associated with DM. We examined the effect of high glucose, fatty acids and NO donor on basal and SDF–1 induced migration of CD34+ cells from DM patients with nonproliferative diabetic retinopathy (NPDR) compared to controls. Methods: Peripheral blood was obtained from patients with NPDR (n=42) and healthy volunteers (n=19). Mononuclear cells (MNCs) were separated from whole blood with centrifugation in CPT tubes. CD34+ cells were isolated from separated MNCs using magnetic microbeads. Migration assays were performed using Boyden chambers. Results: CD34+ cells from normals showed a biphasic response to SDF–1, with peaks at 0.01nM and 100nM. However, CD34+ cells from diabetes patients showed a flat response. This defect in migration was associated with an increase in cell surface activity of CD26 dipeptidyl peptidase, an enzyme that inactivates SDF–1. Pretreatment of diabetic CD34+ cells with the NO donor, DETE–NO ameliorated the defect in CD34+ cell migration to SDF–1 by decreasing cell surface activity of CD 26 and decreasing SDF–1 degradation. Moreover pretreatment with polyunstaturated fatty acids, such as linoleic and arachidonic acid, stimulated migration in response to SDF–1. Pretreatment with high glucose had no effect on EPC migration. Conclusions: We demonstrate that CD34+ cells isolated from patients with NPDR have a marked defect in migration to SDF–1. This defect is possibly due to an increased cell surface activity of the SDF–1 inactivating enzyme, CD26 dipeptidyl peptidase. Incubation with a NO donor ameliorates the defect of CD34+ cells to SDF–1 by decreasing CD26 dipeptidyl peptidase activity and reducing SDF–1 degradation. Pretreatment with polyunsaturated fatty acids promote CD34 migration and could correct DM associated dysfunction. Correction of CD34 dysfunction could facilitate endothelial cell repair and prevent the development of acellular capillaries in diabetic patients.
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