Low Dose Decitabine Assists Mesenchymal Stem Cells To Promote Islets Restoration In Type 2 Diabetic Mice

Backgrouds:Type 2 diabetes is characterized by chronic inflammation,and chronic inflammatory environment in islets contributes to ?-cell dysfunction.Mesenchymal stem cells(MSCs)are multi-potent adult stem cells with self-renewal ability,multi-directional differentiation potential and immunomodulatory effect.MSCs could promote islets restoration and decrease blood glucose levels by regulating the phenotype of macrophages and alleviating intra-islet inflammation.However,animal experiments and clinical studies both found that anti-diabetic effect of a single MSCs infusion is relatively transient.Decitabine(DAC)is an epigenetic modifier and has immunomodulatory ability to promote macrophages polarization towards anti-inflammatory type at low doses,thereby preventing or treating some inflammatory diseases.Methods:We investigated that compared with MSCs infusion alone,whether the combination of low-dose DAC and a single infusion of UC-MSCs could augment islet restoration and enhance the anti-diabetic effect in type 2 diabetic mice induced by high-fat diets and STZ injection.In vitro,we investigate the effect of DAC and UC-MSCs on macrophages phenotypes and cytokines expression of macrophages.Results:1 week after treatment,the blood glucose level of combination treatments group(MSCs+DAC group,MD group)was similar to that of MSCs group,and DAC alone didn't decrease blood glucose levels.However,4 weeks after treatments,the blood glucose level of MD group maintained lower than MSCs group.The serum fasting insulin concentration,IPGTT and ITT results of MD group were also better than those of MSCs group.Islet immunofluorescence staining showed that MD treatments prolonged islets restoration.In addition,MD treatments resulted in lower IL-1? expression?fewer pro-inflammatory macrophages and more anti-inflammatory macrophages in islets,suggesting islet restoration in MD group was correlated with the macrophage polarization.In vitro,we found that MSCs promoted murine macrophages polarization towards the anti-inflammatory phenotype and reduced the expression of pro-inflammatory cytokines.The combination of DAC and MSCs can further promote the polarization of macrophages towards anti-inflammatory phenotype,accompanied by increased expression of PI3K/AKT signaling pathways in macrophages.After adding PI3K signaling pathway inhibitor LY294002,the polarization of macrophages was partly blocked,suggesting that PI3K/AKT pathway contributed to MD-induced macrophages polarization.Conclusion:The combination of low-dose DAC and a single UC-MSCs infusion can prolong islet restoration and anti-diabetic effect,which is probably attributed to the polarization of macrophages towards anti-inflammatory phenotype in islets.This study has enriched therapeutic strategies of type 2 diabetes and provides new prospects for the clinical application of stem cells therapy.