Abstract 228: Short-term Cyclosporine Therapy Increases Ischemia-induced Endothelial Progenitor Cell Mobilization Through Manipulation Of The CD26 System
Cyclosporine A (CsA), an immunosuppressant, has remarkably improved the short-term success rate of transplantation. The CD26/dipeptidylpeptidase IV (DPP IV) system plays a critical role in mobilizing endothelial progenitor cells (EPCs) from bone marrow. This study investigated whether CsA manipulates CD26/DPP IV activity and increases EPC mobilization. C57 BL/6 mice were divided into control and CsA-treated groups. Circulating EPCs were enumerated before and after hindlimb ischemia was induced. Levels of stroma-derived factor-1α (SDF-1α), stem cell factor (SCF), vascular endothelial grow factor (VEGF), and granulocyte-colony stimulating factor (G-CSF) were measured in the blood. Compared to the controls, CsA treatment significantly increased the serum levels of SDF-1α and SCF (p < 0.001), but not of VEGF or G-CSF after ischemic stress. The CsA group displayed a significant increase in the number of circulating EPCs (with a 7-fold increase in sca-1+KDR+ cells and a 1.5-fold increase in c-kit+CD31+ cells versus the controls at 18 h after ischemia was induced, both p < 0.05). In vivo, CsA also caused 2- and 5-fold increases in the numbers of bone marrow-derived EPCs incorporated into the Matrigel and ischemic limbs, respectively (p < 0.05). In the peripheral blood, CsA significantly decreased CD26+ cell numbers (p < 0.001) and attenuated the plasma CD26/DPP IV activity (p < 0.001). CsA did not alter the acitivty of MMP-2 or MMP-9 in vitro or in vivo. Compared to the controls, short-term CsA treatment significantly improved the perfusion of ischemic limbs and decreased the spontaneous digital amputation rate. In conclusions, this study demonstrated that CsA manipulates the mobilization of bone marrow-derived EPCs into the circulation via the CD26/DPP IV system. Short-term CsA treatment has beneficial effects on angiogensis of ischemic tissues.