Background

α-cell dysregulation gives rise to fasting and postprandial hyperglycemia in type 2 diabetes mellitus(T2DM). Administration of Mesenchymal stem cells (MSCs) or their conditioned medium can improve islet function and enhance insulin secretion. However, studies showing the direct effect of MSCs on islet α-cell dysfunction are limited.

Methods

In this study, we used high-fat diet (HFD)-induced mice and α-cell line exposure to palmitate (PA) to determine the effects of bone marrow-derived MSC-conditioned medium (bmMSC-CM) on glucagon secretion. Plasma and supernatant glucagon were detected by enzyme-linked immunosorbent assay(ELISA). To investigate the potential signaling pathways, phosphatase and tensin homolog deleted on chromosome 10 (PTEN), AKT and phosphorylated AKT(p-AKT) were assessed by Western blotting.

Results

In vivo, bmMSC-CM infusion improved the glucose and insulin tolerance and protected against HFD-induced hyperglycemia and hyperglucagonemia. Meanwhile, bmMSC-CM infusion ameliorated HFD-induced islet hypertrophy and decreased α- and β-cell area. Consistently, in vitro, glucagon secretion from α-cells or primary islets was inhibited by bmMSC-CM, accompanied by reduction of intracellular PTEN expression and restoration of AKT signaling. Previous studies and the TargetScan database indicate that miR-181a and its target PTEN play vital roles in ameliorating α-cell dysfunction. We observed that miR-181a-5p was highly expressed in BM-MSCs but prominently lower in αTC1-6 cells. Overexpression or downregulation of miR-181a-5p respectively alleviated or aggravated glucagon secretion in αTC1-6 cells via the PTEN/AKT signaling pathway.

Conclusions

Our observations suggest that MSC-derived miR-181a-5p mitigates glucagon secretion of α-cells by regulating PTEN/AKT signaling, which provides novel evidence demonstrating the potential for MSCs in treating T2DM.

中文翻译：

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间充质干细胞条件培养基通过 miR-181a-5p 及其靶标 PTEN/AKT 信号传导缓解高脂肪诱导的高血糖素血症

 背景

α 细胞失调会导致 2 型糖尿病 (T2DM) 的空腹和餐后高血糖。施用间充质干细胞（MSC）或其条件培养基可以改善胰岛功能并增强胰岛素分泌。然而，表明 MSC 对胰岛 α 细胞功能障碍的直接影响的研究有限。

 方法

在这项研究中，我们使用高脂饮食 (HFD) 诱导的小鼠和 α 细胞系暴露于棕榈酸酯 (PA) 来确定骨髓来源的 MSC 条件培养基 (bmMSC-CM) 对胰高血糖素分泌的影响。采用酶联免疫吸附试验（ELISA）检测血浆和上清液胰高血糖素。为了研究潜在的信号通路，通过蛋白质印迹法评估了 10 号染色体上缺失的磷酸酶和张力蛋白同源物 (PTEN)、AKT 和磷酸化 AKT (p-AKT)。

 结果

在体内，bmMSC-CM输注改善了葡萄糖和胰岛素耐受性，并预防HFD引起的高血糖和高胰高血糖素血症。同时，bmMSC-CM 输注可改善 HFD 诱导的胰岛肥大并减少 α 和 β 细胞面积。一致地，在体外， bmMSC-CM 抑制 α 细胞或原代胰岛的胰高血糖素分泌，并伴随细胞内 PTEN 表达的减少和 AKT 信号传导的恢复。先前的研究和 TargetScan 数据库表明 miR-181a 及其靶点 PTEN 在改善 α 细胞功能障碍中发挥着重要作用。我们观察到 miR-181a-5p 在 BM-MSC 中高表达，但在 αTC1-6 细胞中显着降低。 miR-181a-5p 的过表达或下调分别通过 PTEN/AKT 信号通路减轻或加重 αTC1-6 细胞中的胰高血糖素分泌。

 结论

我们的观察表明，MSC 衍生的 miR-181a-5p 通过调节 PTEN/AKT 信号传导来减轻 α 细胞的胰高血糖素分泌，这提供了新的证据，证明 MSC 治疗 T2DM 的潜力。