Transplantation of Bone Marrow–Derived Mesenchymal Stem Cells Improves Diabetic Polyneuropathy in Rats

Abstract

OBJECTIVE-Mesenchymal stem cells (MSCs) have been reported to secrete various cytokines that exhibit angiogenic and neurosupportive effects. This study was conducted to investigate the effects of MSC transplantation on diabetic polyneuropathy (DPN) in rats.RESEARCH DESIGN AND METHODS-MSCs were isolated from bone marrow of adult rats and transplanted into hind limb skeletal muscles of rats with an 8-week duration of streptozotocin (STZ)-induced diabetes or age-matched normal rats by unilateral intramuscular injection. Four weeks after transplantation, vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) productions in transplanted sites, current perception threshold, nerve conduction velocity (NCV), sciatic nerve blood flow (SNBF), capillary number-to-muscle fiber ratio in soleus muscles, and sural nerve morphometry were evaluated.RESULTS-VEGF and bFGF mRNA expression were significantly increased in MSC-injected thigh muscles of STZ-induced diabetic rats. Furthermore, colocalization of MSCs with VEGF and bFGF in the transplanted sites was confirmed. STZ-induced diabetic rats showed hypoalgesia, delayed NCV, decreased SNBF, and decreased capillary number-to-muscle fiber ratio in soleus muscles, which were all ameliorated by MSC transplantation. Sural nerve morphometry showed decreased axonal circularity in STZ-induced diabetic rats, which was normalized by MSC transplantation. D iabetic polyneuropathy (DPN) is the most common complication of diabetes. It is estimated that ϳ20 -30% of diabetic patients are affected by symptomatic DPN (1). Generally, DPN develops symmetrically in a length-dependent fashion, with dying back or dropout of the longest nerve fibers; both myelinated and unmyelinated, large and small are affected. Diabetic patients suffer from various symptoms of DPN, such as spontaneous pain, hyperalgesia, and diminished sensation (2). It has been shown that tight glycemic control is effective in slowing the progression of DPN but cannot completely prevent it (3). Therefore, additional therapeutic strategies are required. CONCLUSIONS-TheseNeural cell degeneration and decreased nerve blood flow (NBF) have been recognized as pathophysiologically characteristic features of DPN (4). Therefore, therapeutic agents that could act as both neurotrophic and angiogenic factors would be useful for the treatment of DPN even at an advanced stage. We previously demonstrated that local administration of basic fibroblast growth factor (bFGF) by intramusclar injection with crosslinked gelatin hydrogel improved the impaired nerve functions of streptozotocin (STZ)-induced diabetic rats, including amelioration of decreased NBF, hypoalgesia, and the delayed motor nerve conduction velocity (MNCV) on the treated side of sciatictibial nerves and that these effects were maintained for at least 30 days (5). Schratzberger et al. (6) showed that vascular endothelial growth factor (VEGF) gene transfer significantly increased the NCV and NBF as well as the vascular densities in muscle and peripheral nerv...

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