Background: Diabetic nephropathy (DN) is a serious complication of diabetes mellitus and a common cause of end-stage renal disease. Autophagy has a defensive role against kidney damage caused by hyperglycemia. Mesenchymal stem cell (MSC)-derived exosomes are currently considered as a new promising therapy for chronic renal injury. However, the renal-protective mechanism of exosomes on DN is not completely understood. We examined the potential role of MSC-derived exosomes for enhancement of autophagy activity and their effect on DN. In our study, we used five groups of rats: control; DN; DN treated with exosomes; DN treated with 3-methyladenine (3-MA) and chloroquine (inhibitors of autophagy); and DN treated with 3-methyladenine (3-MA), chloroquine, and exosome groups. We assessed renal function, morphology, and fibrosis. Moreover, ratios of the autophagy markers mechanistic target of rapamycin (mTOR), Beclin-1, light chain-3 (LC3-II), and LC3-II/LC3-I were detected. Additionally, electron microscopy was used for detection of autophagosomes. Results: Exosomes markedly improved renal function and showed histological restoration of renal tissues, with significant increase of LC3 and Beclin-1, and significant decrease of mTOR and fibrotic marker expression in renal tissue. All previous effects were partially abolished by the autophagy inhibitors chloroquine and 3-MA. Conclusion: We conclude that autophagy induction by exosomes could attenuate DN in a rat model of streptozotocin-induced diabetes mellitus.
BackgroundMesenchymal stem cells (MSCs) have diverse functions in regulating injury and inflammation through the secretion of extracellular vesicles (EVs).MethodsIn this study, we investigated the systemic administration of extracellular vesicles derived from human umbilical cord mesenchymal stem cells (UCMSCs-EVs) as a therapeutic agent for intrauterine adhesions (IUAs) caused by endometrial injury. Additionally, we investigated the therapeutic impact of both UCMSCs-EVs and estrogen either separately or in combination in a rat model. The inflammation, vascularization, proliferation, and extent of fibrosis were assessed by a histopathological and immunohistochemical assessment using transforming growth factor (TGF)-β as a fibrotic marker and vascular endothelial growth factor (VEGF) as a vascular marker. Additionally, quantitative real-time polymerase chain reaction (qRT-PCR) was used to analyze the expression of tumor necrosis factor (TNF)-α, interleukin (IL)-1, IL-6 (inflammatory cytokines), CD140b (a marker of endometrial stem cells), and RUNX2 (an antifibrotic factor). Finally, Western blotting was used to evaluate collagen I and β-actin expression.ResultsThe therapeutic groups treated with either UCMSCs-EVs alone or combined with estrogen exhibited a significant decrease in inflammation and fibrosis (TNF-α, TGF-β, IL-1, IL-6, RUNX2, and collagen-I) as well as a significant decrease in vascularization (VEGF) compared with the untreated rats with IUAs. The most significant results were obtained in animals with IUAs that received a combined therapy of UCMSCs-EVs and estrogen.ConclusionsWe conclude that the synergistic action of human UCMSCs-EVs combined with estrogen provides a highly effective alternative regenerative agent in IUA treatment.
Background Diabetic foot ulceration is a serious chronic complication of diabetes mellitus characterized by high disability, mortality, and morbidity. Platelet-rich plasma (PRP) has been widely used for diabetic wound healing due to its high content of growth factors. However, its application is limited due to the rapid degradation of growth factors. The present study aimed to evaluate the efficacy of combined adipose-derived mesenchymal stem cells (ADSCs) and PRP therapy in promoting diabetic wound healing in relation to the Notch signaling pathway. Methods Albino rats were allocated into 6 groups [control (unwounded), sham (wounded but non-diabetic), diabetic, PRP-treated, ADSC-treated, and PRP+ADSCs-treated groups]. The effect of individual and combined therapy was evaluated by assessing wound closure rate, epidermal thickness, dermal collagen, and angiogenesis. Moreover, gene and protein expression of key elements of the Notch signaling pathway (Notch1, Delta-like canonical Notch ligand 4 (DLL4), Hairy Enhancer of Split-1 (Hes1), Hey1, Jagged-1), gene expression of angiogenic marker (vascular endothelial growth factor and stromal cell-derived factor 1) and epidermal stem cells (EPSCs) related gene (ß1 Integrin) were assessed. Results Our data showed better wound healing of PRP+ADSCs compared to their individual use after 7 and 14 days as the combined therapy caused reepithelialization and granulation tissue formation with a marked increase in area percentage of collagen, epidermal thickness, and angiogenesis. Moreover, Notch signaling was significantly downregulated, and EPSC proliferation and recruitment were enhanced compared to other treated groups and diabetic groups. Conclusions These data demonstrated that PRP and ADSCs combined therapy significantly accelerated healing of diabetic wounds induced experimentally in rats via modulating the Notch pathway, promoting angiogenesis and EPSC proliferation.
Background: diabetic nephropathy (DN) is a serious complication of diabetes mellitus and a common cause for end stage renal disease. Autophagy has a defensive role against kidney damage caused by hyperglycemia. The mesenchymal stem cells (MSCs) derived exosomes are currently considered as a new promising therapy in chronic renal injury. However, the renal protective mechanism of exosomes on DN has not been completely understood. We examined the potential role of MSCs derived exosomes in enhancement of autophagy activity and its effect on DN. In our study we used five groups of rats; control, DN, DN treated with exosomes, DN treated with 3-methyladenine (3-MA) and chloroquine (inhibitors of autophagy) and DN treated with 3-methyladenine (3-MA) and chloroquine and exosomes groups. We assessed renal functions, morphology and fibrosis. Moreover, autophagy markers; mTOR, Beclin-1, light chain-3 (LC3-II), and LC3-II/LC3-I ratio were detected. Additionally, electron microscopy was used for detection of autophagosomes. Results: Exosomes markedly improved the renal functions and showed histological restoration of renal tissues with significant increase in LC3 and Beclin-1 besides the significant decrease in mTOR and fibrotic markers expression in renal tissue. All previous effects were partially abolished by the autophagy inhibitor, chloroquine and 3-MA. Conclusions: we conclude that autophagy induction by exosomes could attenuate DN in a rat model of streptozotocin-induced diabetes mellitus.
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