Despite dramatic advances in anatomic knowledge and surgical technique a number of wounds defy the ability of the reconstructive microsurgeon to achieve closure. Often such wounds are ischemic and in watershed areas. Restoring adequate soft tissue perfusion in such wounds requires novel solutions. Recently several factors have been identified (i.e. VEGF, PIGF) which stimulate angiogenesis in ischemic wounds. However, sustained and targeted delivery of such agents remains problematic. To overcome this we evaluated the ability of hematopoietic stem cells to be mobilized under conditions of system stress and to localize to areas of angiogenis. An oncologic model was utilized since it is know that tumor growth is dependent on angiogenesis. Female BALB/c mice were injected with a syngenic breast cancer cell line to the mammary fat pad. Control animals received saline injection to the fat pad. Animals were matched for age and tumor-bearing interval. At sacrifice peripheral blood, spleen and tumor tissues were harvested and low density mononuclear cells separated via density gradient centrifugation. Total cell number, viability, ability to replicate, and ability to destroy foreign cells was determined by standard techniques and assays. Mobilization of hematopoietic stem cells was quantified by colony-forming unit assay (CFU-C) and FACS analysis using appropriate cell surface markers. Finally, levels of angiogenic/chemotactic cytokines including G-CSF, TGF-a, IL-2 and Ftl-3 ligand were measured in plasma of tumor-bearing animals and conditioned medium from cultured tumor cells. In tumor-bearing animals low density mononuclear cells were increased in all tissue compartments versus controls as a function of tumor-bearing interval. Likewise hematopoietic stem cells were mobilized in progressively increasing numbers to all tissue compartments as a function of tumor burden. Most important though was the demonstration of endothelial stem cells among the low density mononuclear cells isolated from tumors. Concurrent with stem cell mobilization to all tissue compartments, angiogenic and chemotactic cytokine levels were increased in both plasma of tumor-bearing animals and conditioned medium from tumor cell cultures as compared to controls. The above results demonstrate the ability of stem cells, under cytokine stimulation, to mobilize to areas of angiogenic activity such as that occurs during the neovascularization of growing tumors. Future studies are underway to evaluate the ability of hematopoietic stem cells, and especially endothelial stem cells, to mobilize to other areas of angiogenesis such as healing wounds and areas of acute, sub-acute and chronic tissue hypo-perfusion, and for such cells to deliver biologically active molecules.