| Progressive pancreatic ?-cell dysfunction is recognized as a fundamental pathology of type 2 diabetes(T2D).Recently,mesenchymal stem cells(MSCs)have been identified in protection of islets function in T2D individuals.However,the underlying mechanisms remain elusive.It is widely accepted that ?-cell dysfunction is closely related to improper accumulation of macrophages in the islets,and a series of reports suggest that MSCs possess great immunomodulatory properties by which they could elicit macrophages into an anti-inflammatory M2 state.In this study,we induced a T2D mouse model with a combination of high-fat diet(HFD)and low-dose streptozotocin(STZ),and then performed human umbilical cord-derived MSCs(UC-MSCs)infusion to investigate whether the effect of MSCs on islets protection was related to regulation on macrophages in pancreatic islets.UC-MSCs infusion exerted great anti-diabetic effects and significantly promoted islets recovery in T2D mice.Interestingly,pancreatic inflammation was remarkably suppressed,and local Ml macrophages were directed towards an anti-inflammatory M2-like state after UC-MSC infusion.In vitro study also proved that UC-MSCs inhibited the activation of the M1 phenotype and induced the generation of the M2 phenotype in isolated mouse bone marrow derived macrophages(BMDMs),peritoneal macrophages(PMs)and THP-1 cells.Further analysis showed that Ml-stimulated UC-MSCs increased the secretion of interleukin(IL)-6,blocking which largely abrogated the UC-MSCs effects on macrophages both in vitro and in vivo,resulting in dampened restoration of ?-cell function and glucose homeostasis in T2D mice.In addition,Monocyte chemoattractant protein-1(MCP-1)was found to work in accordance with IL-6 in directing macrophage polarization from M1 to M2 state.Efficient cell therapy largely relies on appropriate homing to target tissues.Considering that T2D is a metabolic disease,and damage of multiple tissues is involved,therefore,knowing where and to what extent injected UC-MSCs have homed is critically important.However,bio-distribution data for UC-MSCs in T2D subjects are extremely limited.Beneficial effects of UC-MSCs on T2D subjects are found to be associated with increased M2 macrophages,but no systemic evaluation of M2 macrophages has been performed in T2D individuals.Therefore,we further treated T2D mice with CM-Dil-labeled UC-MSCs,systematically evaluated the homing of UC-MSCs and analyzed their subsequent modulation on macrophage polarization in T2D mice.To compare UC-MSCs migration between T2D and normal subjects,a collection of normal mice also received UC-MSC transplantation.UC-MSCs were found to home to the lung,liver and spleen in both normal and T2D recipients.Specifically,the spleen harbored the largest number of UC-MSCs.Unlike normal mice,a certain number of UC-MSCs also homed to pancreatic islets in T2D mice,which suggested that UC-MSC homing may be closely related to tissue damage.Moreover,the number of M2 macrophages,not only in islets,but also in liver,fat and muscle significantly increased after UC-MSC infusion,which implied a strong link between the increased M2 macrophages and the improved condition in T2D mice.An increase in M2 macrophages was also observed in the spleen,suggesting that UC-MSCs might exert systemic effects in T2D individuals by modulating macrophages in immune organs.These data may not only provide novel insights into intervention methods and therapeutic targets for the clinical application of UC-MSCs in the treatment of T2D,but also provide precious information for other inflammation-related diseases such as rheumatoid arthritis and inflammatory bowel disease. |
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