Low-energy shock wave for enhancing recruitment of endothelial progenitor cells - A new modality to increase efficacy of cell therapy in chronic hind limb ischemia

Background - Stem and progenitor cell therapy is a novel approach to improve neovascularization and function of ischemic tissue. Enhanced tissue expression of chemoattractant factors such as stromal cell - derived factor 1 and vascular endothelial growth factor is crucial for the recruitment of circulating endothelial progenitor cells (EPCs) during acute ischemia. In chronic ischemia, however, expression of these chemoattractants is less pronounced, which results in insufficient EPC recruitment into the target tissue. Therefore, we investigated the effect of targeted extracorporeal shock wave (SW) application in order to facilitate EPC recruitment into nonischemic and chronic ischemic tissue. Methods and Results - Hind limb adductor muscles of nude rats were treated with 500, 1000, and 2000 impulses of focused low-energy SW (flux density level: 0.05 mJ/mm(2)). Twenty-four hours later, mRNA expression of the chemoattractant stromal cell - derived factor 1 was significantly increased with 1000 impulses (stromal cell derived factor 1/GAPDH: 0.95 +/- 0.09) and 2000 impulses (stromal cell-derived factor 1/GAPDH: 1.17 +/- 0.24; both P < 0.05 versus untreated). Histologically, the number of vascular endothelial growth factor-positive endothelial cells per myocyte was significantly increased with 2000 impulses (0.24 +/- 0.05 versus 0.09 +/- 0.02; P < 0.01). This preconditioning effect resulted in significantly enhanced recruitment and homing of EPCs that were intravenously infused 24 hours after SW treatment (P < 0.05). In a rat model of chronic hind limb ischemia, SW-facilitated EPC treatment resulted in a significant increase in relative blood flow recovery as assessed by laser Doppler imaging (P < 0.05). Conclusions - Preconditioning of both nonischemic and chronic ischemic tissue with low-energy SW improves recruitment of circulating EPCs via enhanced expression of chemoattractant factors. Thus, SW-facilitated cell therapy may improve the efficacy of EPC treatment in patients with chronic ischemia.