Low-Dose Decitabine Assists Human Umbilical Cord-Derived Mesenchymal Stem Cells in ProtectingβCells via the Modulation of the Macrophage Phenotype in Type 2 Diabetic Mice

Abstract

Background. Progressive β-cell dysfunction, a major characteristic of type 2 diabetes (T2D), is closely related to the infiltration of inflammatory macrophages within islets. Mesenchymal stem cells (MSCs) have been identified to alleviate β-cell dysfunction by modulating macrophage phenotype in T2D, but the restoration of β-cells by a single MSC infusion is relatively transient. Decitabine (DAC) has been reported to polarize macrophages towards the anti-inflammatory phenotype at low doses. We therefore investigated whether low-dose decitabine could enhance the antidiabetic effect of MSCs and further promote the restoration of β-cell function. Methods. We induced a T2D mice model by high-fat diets and streptozotocin (STZ) injection. Mice were divided into five groups: the normal group, the T2D group, the DAC group, the MSC group, and the MSC plus DAC group (MD group). We examined the blood glucose and serum insulin levels of mice 1, 2, and 4 weeks after MSC and/or DAC treatment. Dynamic changes in islets and the phenotype of intraislet macrophages were detected via immunofluorescence. In vitro, we explored the effect of MSCs and DAC on macrophage polarization. Results. The blood glucose and serum insulin levels revealed that DAC prolonged the antidiabetic effect of MSCs to 4 weeks in T2D mice. Immunofluorescence staining demonstrated more sustainable morphological and structural amelioration in islets of the MD group than in the MSC group. Interestingly, further analysis showed more alternatively activated macrophages (M2, anti-inflammatory) and fewer classically activated macrophages (M1, proinflammatory) in islets of the MD group 4 weeks after treatment. An in vitro study demonstrated that DAC together with MSCs further polarized macrophages from the M1 to M2 phenotype via the PI3K/AKT pathway. Conclusion. These data unveiled that DAC prolonged the antidiabetic effect of MSCs and promoted sustainable β-cell restoration, possibly by modulating the macrophage phenotype. Our results offer a preferable therapeutic strategy for T2D.

Gallic acid Inhibits M1 Macrophage Polarization via Adenosine 5’-Monophosphate-Activated Protein Kinase/Signal Transducers and Activators of Transcription 1 Pathway

“…Macrophages are vital for the immune response and switch between two phenotypes in order to fulfill their role [17,18] . M1 macrophages secrete high levels of proinflammatory cytokines (TNF-α, IL-6, IL-1β) and produce reactive oxygen species through activation of iNOS.…”

Low‐dose decitabine promotes M2 macrophage polarization in patients with primary immune thrombocytopenia via enhancing KLF4 binding to PPARγ promoter

“…As a regular demethylation regimen for myelodysplastic syndrome, DAC has been found to be advantageous in multiple myeloproliferative diseases such as Hodgkin lymphoma and acute myelogenous leukemia by regulating immune response. 39 , 40 Recently, growing evidence has indicated that low‐dose DAC‐induced M2 macrophage polarization could ameliorate acute lune injury 41 and atherosclerosis, 42 implying the potential role of DAC on immunological disorders. The aberrant DNA methylation has been found to participate in the pathophysiology of ITP, 43 targeting the DNA methylation could be used as a new treatment for ITP.…”

Human umbilical cord mesenchymal stem cells in diabetes mellitus and its complications: applications and research advances

“…MCP-1 secreted by HUC-MSCs synergistically regulates macrophage polarisation with IL-6 71 . Additionally, low-dose decitabine may prolong the antidiabetic effects of MSCs and promote sustainable β-cell recovery by polarising macrophages to the M2 phenotype 72 . Overall, HUC-MSCs can reduce islet β-cell inflammation by polarising macrophages to the M2 anti-inflammatory phenotype, thereby alleviating islet dysfunction in patients with DM.…”