Exogenous bone marrow-derived cells (BMDCs) are promising therapeutic agents for the treatment of tissue ischemia and traumatic injury. However , until we identify the molecular mechanisms that underlie their actions , there can be no rational basis for the design of therapeutic strategies using BMDCs. The pro-healing effects of BMDCs are apparent very shortly after treatment , which suggests that they may exert their effects by the modulation of acute inflammation. We investigated this hypothesis by taking advantage of the fact that BMDCs from healthy , young, but not obese , diabetic mice stimulate vascular growth. By comparing both in vitro secretion and in vivo local induction of acute phase inflammatory cytokines by these cells , we identified monocyte chemoattractant factor 1 and tumor necrosis factor ␣ as potential mediators of BMDC-induced tissue repair. In vivo analysis of BMDC-treated ischemic limbs and cutaneous wounds revealed that the production of monocyte chemoattractant factor 1 by exogenous and endogenous BMDCs is essential for BMDC-mediated vascular growth and tissue healing , while the inability of BMDCs to produce tumor necrosis factor ␣ appears to play a lesser but still meaningful role. Thus, measurements of the secretion of cytokines by BMDCs may allow us to identify a priori individuals who would or would not be good candidates for BMDC-based therapies.

lin− bone marrow‐derived cells could be useful in the treatment of diabetic vascular complications. However, autologous transplant may be problematic. Exogenous non‐diabetic (ND) lin−cells stimulate vascularization of injured tissue in diabetic mice, while diabetic (D) lin−cells do not. This could be due to diabetes induced alterations in the secretion of pro‐angiogenic factors by lin− cells. To test this we compared the secretory profiles of ND‐ and D‐lin−cells. Secretion of TNFα a key pro‐inflammatory/angiogenic cytokine, was reduced in the diabetic cells. To assess TNFα's potential role in lin− cell mediated angiogenesis, we measured its levels and those of its downstream pro‐angiogenic targets (IL‐1β, MCP‐1, and VEGF) in ischemic muscle treated with lin− cells. ND‐lin− cells but not D‐lin− cells increased TNFα, IL1β and MCP‐1 protein levels in diabetic ischemic limbs. Since MCP‐1 recruits monocytes which induce VEGF, we expected, and found monocyte numbers and VEGF levels were higher in the ND‐lin− cell treated limb relative to that of D‐lin− cell treated limb. Thus, ND‐lin− cells may induce vascularization by modulating inflammation through secretion of TNFα. Consistent with this TNFα−/− lin− cells failed to stimulate VEGF production and vessel growth in the skin wounds. Hence, down‐regulation of TNFα in diabetic lin− cells may contribute to their inability to stimulate vascular growth. DK55965 and DK59223