Molecular Repair of Diabetic Mesenchymal Stem Cells (dMSC) for Peripheral Arterial Disease

Veterans Health Administration, Decatur PA

Investigators

Linked publications, trials & patents

Abstract

Background and Innovation: Diabetes and ischemia lead to loss of neuromotor connections resulting in disability. Diabetic Veterans with PAD have significant therapeutic needs that are often incompletely addressed due to limitations in our understanding and therapeutic options. Functional recovery of ischemic muscle is the goal of this proposal. Innovative aspects of our approach include: 1) determining mechanistically the epigenetic opportunities that exist in diabetic mesenchymal stem cells, which may be useful in a number of pathologies affecting Veterans with diabetes; 2) defining the role of macrophage subsets on re-innervation of new muscle, how this is disrupted by diabetic conditions, and then testing how cell therapy may be able to direct the desired macrophage mediators to more rapidly and/or more completely re-innervation new muscle. Significance and impact to Veteran Healthcare: Diabetes and peripheral arterial disease disproportionately affect our nation’s Veterans. Diabetic patients have limited collateralization and regenerative capacity in their tissues. Diabetic patients with peripheral arterial disease also have severe ischemic myopathy and de- innervation that impacts their functional ability to walk. Regenerative cell-based therapies may enable a full step forward in establishing functional recovery of the vascular supply and skeletal muscle, including reformation of the neuromotor junctions necessary for functional recovery. We have identified a unique intracellular signaling defect in diabetic mesenchymal stem cells that is epigenetically modifiable, enabling autologous cell therapy in diabetic patients. This proposal will test the epigenetic regulators of these favorable changes in diabetic mesenchymal stem cells, the role of the innate immune cells in the reformation of neuromotor junctions, and then test the capacity of diabetic mesenchymal stem cells to empower functional regeneration of muscle under diabetic conditions using relevant in vitro and in vivo models. Path to translation/implementation: Promising results from this work will provide a number of translational opportunities for Veterans with diabetes, including the development of epigenetic therapeutics for diabetic mesenchymal stem cells and patients, development/testing of novel therapeutics for ischemic myopathy/re- innervation of diabetic muscle, and the role of immunomodulatory therapies in large animal and first in Veteran testing.