Diabetes and peripheral arterial disease (PAD) disproportionately affect our nation's Veterans. Diabetic patients have limited collateralization and regenerative capacity in their tissues. Diabetic patients with peripheral arterial disease have severe ischemic complications and are at grave risk of major amputation. Reversing tissue ischemia by surgical revascularization prevents amputations, but many patients with diabetes and peripheral arterial disease are not fully treatable by surgical revascularization. Regenerative cell-based therapies may enable a full step forward in re-establishing or regenerating the vascular supply of the leg to prevent amputations. We have identified a unique intracellular signaling defect in diabetic mesenchymal stem cells that can be favorably modified to improve these cells. This proposal will test the effectiveness, durability and then mechanism by which this approach works under diabetic conditions using relevant in vitro and in vivo models. Positive results will be used to translate these methods to Veterans with diabetes and PAD.