Transfusion of CXCR4-Priming Endothelial Progenitor Cells Reduces Cerebral Ischemic Damage and Promotes Angiogenesis and Neurogenesis in db/db Diabetic Mice

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Previous studies suggest that reduction and dysfunction of circulating endothelial progenitor cells (EPCs), and dysregulation in stromal cell derived factor-1/CXC-chemokine receptor 4 (SDF-1/CXCR4) axis in diabetes could be therapeutic targets for diabetic ischemic stroke. This study investigated the efficacy of CXCR4-priming EPCs on cerebral repair following ischemic stroke in db/db diabetic mice. Bone marrow derived EPCs from db/+ control mice were transfected with adenovirus (1x107 IU) carrying CXCR4 (Ad-CXCR4-EPCs) or null (Ad-null-EPCs). The db/db mice were divided into three groups for EPCs injection (2x105 cells/100µl): Ad-CXCR4-EPCs, Ad-null-EPCs or saline (vehicle), via tail vein 2 hrs after middle cerebral artery occlusion (MCAO) surgery. Cerebral blood flow (CBF) was measured with laser Doppler flowmeter. Mice were sacrificed at 2 or 7 days thereafter. Level of circulating EPCs was measured by flow cytometry. Ischemic damage, cerebral microvascular density (MVD), angiogenesis and neurogenesis were determined by histological staining with Fluoro-J, CD31, CD31+BrdU, NeuN+BrdU, GFAP+BrdU, respectively. Results (table) showed: 1) Levels of CXCR4 expression were reduced in the brain and EPCs of db/db mice as measured by real-time RT-PCR and western blot analyses (data not shown); 2) The level of circulating EPCs was more in the mice treated with Ad-CXCR4-EPCs; 3) EPC transfusion improved CBF, increased MVD, angiogenesis and neurogenesis in peri-infarct area, and decreased ischemic damage. The efficacies were better in Ad-CXCR4- EPCs group. Data suggest that transfusion of Ad-CXCR4-EPCs could be a therapeutic avenue for ischemia stroke in diabetes.


A presentation at the ATVB Annual Meeting, April 28-30, 2011 in Chicago, IL.