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.
Highlights
Progressive decline in β-cell mass and function, a major characteristic of type 2 diabetes (T2D), will inevitably lead to insulin deficiency as the disease progresses [1]
We investigated the antidiabetic effect of UC-Mesenchymal stem cells (MSCs) and DAC in T2D mice induced by high-fat diets and STZ injection
The results of the Intraperitoneal glucose tolerance tests (IPGTTs) and intraperitoneal insulin tolerance tests (IPITTs) indicated that the MSC group and the MD group showed a similar improvement in blood glucose metabolism and insulin sensitivity one week after treatment, but the MD group exhibited a better performance 4 weeks after treatment, consistent with the blood glucose levels (Figures 1(c) and 1(d))
Summary
Progressive decline in β-cell mass and function, a major characteristic of type 2 diabetes (T2D), will inevitably lead to insulin deficiency as the disease progresses [1]. Despite the possible role of dipeptidyl peptidase-IV (DPP-IV) inhibitors and glucagonlike peptide-1 (GLP-1) receptor agonists in enhancing β-cell function in rodents, the effect of these drugs on human islets has not been fully confirmed [3, 4]. This highlights the need to find new therapies targeting the fundamental pathogenesis of T2D. The blood glucose and serum insulin levels revealed that DAC prolonged the antidiabetic effect of MSCs to 4 weeks in T2D mice. These data unveiled that DAC prolonged the antidiabetic effect of MSCs and promoted sustainable β-cell restoration, possibly by modulating the macrophage phenotype.
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