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.

中文翻译：

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低剂量地西他滨通过调节 2 型糖尿病小鼠的巨噬细胞表型，帮助人脐带来源的间充质干细胞保护 β 细胞。

背景。进行性β细胞功能障碍是 2 型糖尿病 (T2D) 的主要特征，与胰岛内炎性巨噬细胞的浸润密切相关。间充质干细胞 (MSCs) 已被确定通过调节 T2D 中的巨噬细胞表型来缓解β细胞功能障碍，但通过单次 MSC 输注恢复β细胞是相对短暂的。据报道，地西他滨 (DAC) 在低剂量时可使巨噬细胞向抗炎表型极化。因此，我们研究了低剂量地西他滨是否可以增强 MSCs 的抗糖尿病作用并进一步促进β细胞功能的恢复。方法. 我们通过高脂饮食和链脲佐菌素 (STZ) 注射诱导了 T2D 小鼠模型。将小鼠分为五组：正常组、T2D组、DAC组、MSC组和MSC加DAC组（MD组）。我们在 MSC 和/或 DAC 治疗后 1、2 和 4 周检查了小鼠的血糖和血清胰岛素水平。通过免疫荧光检测胰岛的动态变化和胰岛内巨噬细胞的表型。在体外，我们探讨了 MSCs 和 DAC 对巨噬细胞极化的影响。结果. 血糖和血清胰岛素水平显示，DAC 在 T2D 小鼠中将 MSCs 的抗糖尿病作用延长至 4 周。免疫荧光染色显示 MD 组胰岛的形态和结构改善比 MSC 组更持久。有趣的是，进一步的分析显示，治疗 4 周后，MD 组的胰岛中有更多的交替活化巨噬细胞（M2，抗炎）和更少的经典活化巨噬细胞（M1，促炎）。一项体外研究表明，DAC 与 MSC 一起通过 PI3K/AKT 通路进一步将巨噬细胞从 M1 极化为 M2 表型。结论。这些数据揭示了 DAC 延长了 MSCs 的抗糖尿病作用并促进了可持续的β-细胞恢复，可能通过调节巨噬细胞表型。我们的结果为 T2D 提供了一种更好的治疗策略。