Abstract 1017: Local Transplantation of Endothelial Progenitor Cells Reverses Experimental Diabetic Neuropathy by Augmenting Neovascularization and Providing Angio-neurotrophic Cytokines
Background : Bone marrow(BM)-derived endothelial progenitor cells(EPCs) have been shown to effectively treat various ischemic cardiovascular diseases. Recent evidence has suggested that the pathogenesis of diabetic neuropathy(DN) is related to impaired neovascularization and deficiency of angiogenic and neurotrophic factors. We sought to investigate whether DN could be attenuated by treatment of BM-derived EPCs.
Methods and Results: Severe peripheral neuropathy, characterized by significant slowing of motor nerve conduction velocities (MCV) developed 12 wks after the induction of diabetes with streptozotocin in C57Bl mice (vs normal mice; 43 ± 5 vs 66 ± 3 m/s, p<0.05). These mice were randomly assigned to EPC or saline injection groups (n=25, each group) and received either 1x106 EPCs or saline around the sciatic nerves. In the EPC group, MCV recovered to normal levels within 8 wks after treatment (EPC vs Saline, 64 ± 5 vs 44 ± 3 m/s, p<0.05). Microvascular circulation of sciatic nerve, measured by laser Doppler perfusion imaging, was markedly increased only in the EPC group. Capillary density at 8 wks post-treatment was significantly higher in the EPC group than in the saline group (29 ± 4 vs 20 ± 4 /HPF, p<0.05), Robust engraftment of EPCs was found in sciatic nerves for at least 8 wks. Engrafted EPCs were colocalized with endothelial markers suggestive of transdifferentiation of EPCs into endothelial cells (vasculogenesis) in the vasa nervorum. Higher numbers of BrdU-positive endothelial cells, and lower numbers of TUNEL- positive endothelial cells were observed in the sciatic nerves of the EPC group. Real-time RT-PCR of sciatic nerves revealed that mRNA expression levels of the following cytokines were significantly increased in the EPC group compared to the saline group: VEGF (2.4-fold), FGF-2 (1.4), BDNF (4.2), Shh(2.0), Gli(2.6) and SDF-1α (1.9) (all p<0.05). Protein levels (VEGF, FGF-2, Gli) correlated well with mRNA expression levels.
Conclusions: Local transplantation of BM-derived EPCs could reverse experimental DN by augmenting neovascularization and increasing angiogenic and neurotrophic factors in peripheral nerrves. These novel findings suggest that EPC transplantation may represent an innovative therapeutic option for treating DN.