Diabetic neuropathy (DN) is the most common complication in type 2 diabetes (T2D), affecting up to 50% of diabetic patients. Analysis of microarray and RNA-Seq data has identifi ed genes and pathways associated with DN in murine models; however, these previous transcriptome studies only examined specifi c time-points and longitudinal studies of DN pro gression are lacking. In the current study, we examined genes and path ways related to DN progression over time in dorsal root ganglia (DRG) and

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... ciatic nerve (SCN) of C57BKS db/db mice, a well-characterized murine model of T2D. Peripheral nerve function was assessed at 8 (early neuropathy), 16 (intermediate neuropathy), and 24 (late neuropathy) weeks of age in control db/+ and diabetic db/db mice, and microarray data from each cohort were used to examine gene expression changes throughout the course of DN. Self-Organizing Maps (SOM), an unbiased clustering method, was used to identify genes demonstrating expression changes that coincided with DN progression in DRG and SCN. Functional and pathway enrichment analyses were performed for gene sets with patterns of interest. Results demonstrated that diabetic mice exhibit robust and progressive neuropathy compared to db/+ mice, with signifi cant changes in hindpaw withdrawal latency, intraepidermal nerve fi ber density, and sciatic motor nerve conduction velocity. SOM analysis identifi ed clusters of genes showing expression patterns correlated with the severity of neuropathy, with increasing or decreasing fold-changes as DN progressed. Specifi cally, the genes IL-2, IL-13, IL-17a, and Csf2 were enriched in infl ammation-associated pathways at 8 weeks in DRG and at 24 weeks in SCN. In addition, there was a 2-fold change in expression of genes enriched in cell death at 24 weeks in DRG and SCN. Together, these analyses identifi ed gene and pathway signatures that may play an important role in DN progression in T2D, and suggest potential pharmaceutical targets to prevent DN development. Murine dermal cells form spheroids in ultra-low attachment culture system. It has been proven that the spheroids contain stem progenitor cells and differentiate into neural crest cells (NCs). Here we investigated the therapeutic effects of the transplantation utilizing the NCs on diabetic polyneuropathy (DPN) using streptozotocin-induced diabetic (D) mice. Dermal cells from 5-week old GFP expressing C57BL/6 male mice with or without diabetes formed spheroids. NCs were induced from the spheroids by co-culturing with PA6 feeder cells for 10 days. NCs (1 x 10 3 cells per cluster) were transplanted into hind limb skeletal muscles of 12-week D and age-matched (N) mice, respectively. Four weeks after the transplantation, expressions of Lin28a, NGF, NT-3, VEGF, bFGF, and PGES-1 in soleus muscles and neurophysiological functions of N and D mice were evaluated. NCs expressed stem cell and neural crest cell markers. After the transplantation, GFP-labeled NCs engrafted mainly as pericytes in the injected muscles and some showed CD34 or αSMA positive. No teratomas were found. D showed impaired thermal sensation (thermal plantar test (TPT); N: 5.5±1.7 s, D: 9.6±3.6) indicating hypo-algesia, and delayed MNCV (N: 53.6±6.9 m/s, D: 36.9±6.7) and SNCV (N: 32.9±4.9 m/s, D: 21.9±2.7), which were signifi cantly ameliorated by NCs transplantation (TPT: 5.2±1.1, MNCV: 48.1±5.5, SNCV: 33.7±5.8). Lin28a, NGF and PGES-1 mRNA expressions increased in transplanted soleus muscle. In conclusion, the cell transplantation using NCs derived from dermal spheroids was safe and effective on DPN, regardless of glucose metabolic conditions of donors. These data suggest that the effectiveness could be resulted from paracrine actions of NGF and Prostaglandin E secreted by NCs. Furthermore, the increased expression of Lin28a might indicate the enrichment of undifferentiated or immature cells in NCs. Erectile dysfunction (ED) worsens in diabetic men. Human umbilical cord blood (HUCB) along with widespread availability and low immunogenicity is a valuable source for stem cell-based therapies. The present study was determined the effect of intracavernous injection of HUCB-mononuclear cells (MNCs) on ED in streptozotocin (STZ)-induced diabetic rats. Thirty adult male Sprague-Dawley rats were divided into three groups: 1.) Control, 2.) STZ (35 mg/kg, i.v., 8-wk)-induced diabetic and 3.) MNCs (1×10 6 cells, intracavernosally)-treated diabetic rats. MNCs isolated from HUCB by the Ficoll-Hypaque technique were given at 4-wk of diabetes. Intracavernosal pressure (ICP)/mean arterial pressure (MAP) ratio and expression of endothelial and neuronal markers, such as endothelial nitric oxide synthase (eNOS), hypoxia-inducible factor (HIF)-1α, vascular endothelium growth factor (VEGF) and neuronal (n) NOS as well as the relative area of collagen to muscle fi bers using immunohistochemistry (IHC), Western blotting and Masson-trichrome staining were determined. Diabetic rats demonstrated signifi cantly reduced ICP/MAP ratio (0.26 ± 0.04) and implanted MNCs restored erectile function in diabetic rats (0.67 ± 0.05) compared to control rats (0.56 ± 0.02, p < 0.01). In bath studies, neurogenic relaxant and contractile responses signifi cantly reduced in the diabetic cavernosal tissues, which was restored by the treatment. nNOS enzyme and smooth muscle to collagen ratio were recovered by the treatment. VEGF and eNOS levels were decreased while HIF-1α levels were increased in the diabetic samples. VEGF and HIF-1α levels were partially normalized by the cell therapy. These results indicate that HUCB-MNCs-treatment may reverse ED via up-regulation of nNOS and VEGFdependent manner involving the cooperative activity of down-regulation of HIF-1α pathway. HUCB-MNCs may be a potential candidate for cell-based therapy in ED of diabetic men.