SAT-184 Diabetic Neuropathy as a Hematopoietic Stem Cell Disease in the Bone Marrow

Diabetic neuropathy, a major complication of diabetes mellitus, is induced at a relatively early stage after the development of diabetes, and progressively worsens throughout life. A number of pathological mechanisms for the development of neuropathy have been proposed, including ischemia, up-regulation of inflammatory cytokines, and the deficiency of nerve growth factor in peripheral nerve tissues. However, therapeutic approaches targeting these proposed mechanisms have yielded little success. We previously identified a mechanism by which aberrant bone marrow-derived cells pathologically expressing proinsulin/TNF-alpha fuse with residential neurons to impair neuronal function. Here we show that hematopoietic stem cells (HSCs) in c-kit (+), Sca-1 (+) and Lineage (-) cells, are the culprits that underlie the pathogenesis of diabetic neuropathy in both streptozotocin-induced type 1 diabetic mice and high fat diet-induced type 2 diabetic mice. Furthermore, the important role for these cells is supported by the fact that transplantation of HSCs from diabetic mice to non-diabetic mice produces diabetic neuronal dysfunction in the recipient mice via cell fusion without hyperglycemia. On the other hand, transplantation of HSCs from non-diabetic mice to non-diabetic mice produces no dysfunction and no cell fusion. In conclusion, we have identified hyperglycemia-induced aberrant HSCs underlie the development of diabetic neuropathy, which may constitute a novel therapeutic target for the treatment of diabetic neuropathy.