Mechanism of umbilical cord mesenchymal stem cells in treating retinopathy of type 1 diabetic mice

Objective To investigate whether human umbilical cord mesenchymal stem cells (hUC-MSCs) can play a role in the treatment of diabetic retinopathy (DR) by affecting Notch signaling pathway and vascular endothelial growth factor receptor 2 (VEGFR-2). Methods Eighty female NOD mice aged 6-8 weeks and weighingt of 20-24 g were randomly divided into diabetes group (group DM) group, insulin group (INS) group (insulin glargine subcutaneous injection, group INS) and mesenchymal stem cells (MSC) group (hUC-MSCs + insulin glargine subcutaneous injection, group MSC) according to random number table after adaptive feeding for 1 week. NOD mice without diabetes were compared as normal control (NC) group (group NC). Each group had 10 mice. Random blood glucose was detected regularly. All the mice were sacrificed after 8 weeks. The number of vascular endothelial nuclei beyond the inner limiting membrane of retina were counted. The mRNA expressions of VEGFR-2 and hairy and enhancer of split related 1 (HESR1), as well as the protein expressions of VEGFR-2 and Notch-1 intracellular domain (NICD) of retina were detected. One-way analysis of variance (ANOVA) was used for comparison among multiple groups. The least-significant difference (LSD)-t test was used for comparison between two groups after ANOVA. Results (1) The difference in the number of endothelial nuclei beyond the inner limiting membrane of retina among four groups was statistically significant (F=57.247, P<0.001). The number was significantly lower in MSC group (2.8±0.5) than that in DM group (6.4±1.0) (P<0.05). (2) There were significant differences in the expression of NICD protein, HESR1 mRNA, VEGFR-2 mRNA and protein of retina among four groups (F=155.076-562.306, all P<0.05). Compared with NC group, the expression of NICD protein (0.38±0.18 vs 1.74±0.11) and HESR1 mRNA (0.29±0.04 vs 1.00±0.00) decreased significantly, the expression of VEGFR2 mRNA (4.11±0.40 vs 1.00±0.00) and protein (1.40±0.85 vs 0.28±0.02) increased significantly in DM group(all P<0.05). Compared with DM group, the expression of NICD protein (1.36±0.05 vs 0.38±0.18) and HESR1 mRNA (0.80±0.02 vs 0.29±0.04) increased significantly, meanwhile the expression of VEGFR2 mRNA (1.80±0.27 vs 4.11±0.40) and protein (0.92±0.10 vs 1.40±0.85) decreased significantly in MSC group (all P<0.05). Conclusion hUC-MSCs may inhibit the formation of retinal neovascularization by activating Notch signaling pathway and inhibiting VEGFR-2, and may be helpful for the treatment of DR. Key words: Diabetic retinopathy; Mesenchymal stem cells; Vascular endothelial growth factor receptor-2; Receptor, Notch1