Background:Diabetic chronic wounds are among the most common and serious complications of diabetes and are associated with significant morbidity and mortality.Endothelial-to-mesenchymal transition(EndMT)is a specific ...Background:Diabetic chronic wounds are among the most common and serious complications of diabetes and are associated with significant morbidity and mortality.Endothelial-to-mesenchymal transition(EndMT)is a specific pathological state in which endothelial cells are transformed into mesenchymal cells in response to various stimuli,such as high glucose levels and high oxidative stress.Acidic fibroblast growth factor(aFGF),which is a member of the fibroblast growth factor family,possesses strong antioxidant properties and can promote the differentiation of mesenchymal stem cells into angiogenic cells.Therefore,we investigated the role of aFGF in EndMT in diabetic wounds and analysed the underlying mechanisms.Methods:A diabetic mouse model was used to verify the effect of aFGF on wound healing,and the effect of aFGF on vascular endothelial cells in a high-glucose environment was examined in vitro.We examined the expression of miR-155-5p in a high-glucose environment and the miR-155 downstream target gene SIRT1 by luciferase reporter assays.Results:aFGF promoted wound closure and neovascularization in a mouse model of type 2 diabetes.In vitro,aFGF inhibited the production of total and mitochondrial reactive oxygen species(ROS)in vascular endothelial cells and alleviated epithelial-mesenchymal transdifferentiation in a high-glucose environment.Mechanistically,aFGF promoted the expression of SIRT1 and the downstream targets Nrf2 and HO-1 by negatively regulating miR-155-5p,thereby reducing ROS generation.Conclusions:In conclusion,our results suggest that aFGF inhibits ROS-induced epithelial-mesenchymal transdifferentiation in diabetic vascular endothelial cells via the miR-155-5p/SIRT1/Nrf2/HO-1 axis,thereby promoting wound healing.展开更多
Background:Diabetic wounds feature a high-glucose and acidic microenvironment that impairs macrophage polarization and healing.Adiposederived stem cell-derived exosomes(ADSC-exos)show therapeutic potential but suffer ...Background:Diabetic wounds feature a high-glucose and acidic microenvironment that impairs macrophage polarization and healing.Adiposederived stem cell-derived exosomes(ADSC-exos)show therapeutic potential but suffer from rapid clearance.This study aimed to develop a smart hydrogel for glucose/pH-responsive ADSC-exos release.Methods:A dual-responsive hydrogel(HAP/OCS/PEG/Ag-E)was fabricated via dynamic triple cross-linking.Characterization included rheometry,mechanical tests,and microscopy.In vitro macrophage polarization was assessed via flow cytometry and Western blot.A diabetic mouse wound model evaluated healing rates,histology,angiogenesis,and inflammation.Proteomics and pathway inhibition studies explored mechanisms.Statistical analysis used t-tests and ANOVA.Results:The hydrogel exhibited excellent self-healing,adhesion,and controlled ADSC-exos release under high-glucose/acidic conditions.It promoted M2 macrophage polarization,reduced pro-inflammatory cytokines(IL-1β,IL-6,TNF-α),and accelerated wound healing with enhanced angiogenesis and collagen deposition.Mechanistically,the hydrogel suppressed the Notch/NF-κB/NLRP3 signaling pathway.Conclusion:The smart hydrogel facilitates diabetic wound healing through microenvironment-responsive ADSC-exos release and Notch/NFκB/NLRP3 pathway inhibition,offering a promising strategy for chronic wound treatment.展开更多
基金supported by the National Natural Science Foundation of China(81971835)the Shanghai Wang Zhengguo Foundation for Traumatic Medicine Growth Factor Rejuvenation Plan(SZYZ-TR-07)the Key Industry Innovation Chain(Cluster)-Social Development Foundation of Shaanxi Province,China(2023-ZDLSF-37).
文摘Background:Diabetic chronic wounds are among the most common and serious complications of diabetes and are associated with significant morbidity and mortality.Endothelial-to-mesenchymal transition(EndMT)is a specific pathological state in which endothelial cells are transformed into mesenchymal cells in response to various stimuli,such as high glucose levels and high oxidative stress.Acidic fibroblast growth factor(aFGF),which is a member of the fibroblast growth factor family,possesses strong antioxidant properties and can promote the differentiation of mesenchymal stem cells into angiogenic cells.Therefore,we investigated the role of aFGF in EndMT in diabetic wounds and analysed the underlying mechanisms.Methods:A diabetic mouse model was used to verify the effect of aFGF on wound healing,and the effect of aFGF on vascular endothelial cells in a high-glucose environment was examined in vitro.We examined the expression of miR-155-5p in a high-glucose environment and the miR-155 downstream target gene SIRT1 by luciferase reporter assays.Results:aFGF promoted wound closure and neovascularization in a mouse model of type 2 diabetes.In vitro,aFGF inhibited the production of total and mitochondrial reactive oxygen species(ROS)in vascular endothelial cells and alleviated epithelial-mesenchymal transdifferentiation in a high-glucose environment.Mechanistically,aFGF promoted the expression of SIRT1 and the downstream targets Nrf2 and HO-1 by negatively regulating miR-155-5p,thereby reducing ROS generation.Conclusions:In conclusion,our results suggest that aFGF inhibits ROS-induced epithelial-mesenchymal transdifferentiation in diabetic vascular endothelial cells via the miR-155-5p/SIRT1/Nrf2/HO-1 axis,thereby promoting wound healing.
基金supported by the Natural Science Foundation of Shaanxi Province(No.2024JC-YBQN-0407)National Natural Science Foundation of China(No.81530064)+3 种基金China Postdoctoral Science Foundation(No.2023 M732753)National Natural Science Foundation of China(No.81772071)National Natural Science Foundation of China(No.82172210)Open Fund of Key Laboratory for Intelligent Nano Materials and Devices of the Ministry of Education NJ2023002(INMD-2023 M01).
文摘Background:Diabetic wounds feature a high-glucose and acidic microenvironment that impairs macrophage polarization and healing.Adiposederived stem cell-derived exosomes(ADSC-exos)show therapeutic potential but suffer from rapid clearance.This study aimed to develop a smart hydrogel for glucose/pH-responsive ADSC-exos release.Methods:A dual-responsive hydrogel(HAP/OCS/PEG/Ag-E)was fabricated via dynamic triple cross-linking.Characterization included rheometry,mechanical tests,and microscopy.In vitro macrophage polarization was assessed via flow cytometry and Western blot.A diabetic mouse wound model evaluated healing rates,histology,angiogenesis,and inflammation.Proteomics and pathway inhibition studies explored mechanisms.Statistical analysis used t-tests and ANOVA.Results:The hydrogel exhibited excellent self-healing,adhesion,and controlled ADSC-exos release under high-glucose/acidic conditions.It promoted M2 macrophage polarization,reduced pro-inflammatory cytokines(IL-1β,IL-6,TNF-α),and accelerated wound healing with enhanced angiogenesis and collagen deposition.Mechanistically,the hydrogel suppressed the Notch/NF-κB/NLRP3 signaling pathway.Conclusion:The smart hydrogel facilitates diabetic wound healing through microenvironment-responsive ADSC-exos release and Notch/NFκB/NLRP3 pathway inhibition,offering a promising strategy for chronic wound treatment.
