Mesenchymal stem cell-conditioned medium alleviates high fat-induced hyperglucagonemia via miR-181a-5p and its target PTEN/AKT signaling
Mesenchymal stem cell-conditioned medium alleviates high fat-induced hyperglucagonemia via miR-181a-5p and its target PTEN/AKT signaling
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间充质干细胞条件培养基通过 miR-181a-5p 及其靶点 PTEN/AKT 信号传导缓解高脂肪诱导的高血糖素血症
DOI：
10.1016/j.mce.2021.111445
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发表时间：
2021
影响因子：
4.1
通讯作者：
Chen Li
中科院分区：
文献类型：
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作者：
Song Jia;He Qin;Guo Xinghong;Wang Lingshu;Wang Jinbang;Cui Chen;Hu Huiqing;Yang Mengmeng;Cui Yixin;Zang Nan;Yan Fei;Liu Fuqiang;Sun Yujing;Liang Kai;Qin Jun;Zhao Ruxing;Wang Chuan;Sun Zheng;Hou Xinguo;Li Wenjuan;Chen Li
背景：2型糖尿病(T2 DM)患者α细胞功能失调可导致空腹和餐后高血糖。骨髓间充质干细胞(MSCs)或其条件培养液可以改善胰岛功能，促进胰岛素分泌。然而，显示骨髓间充质干细胞对胰岛α细胞功能障碍的直接作用的研究有限。方法在本研究中，我们利用高脂饮食诱导的小鼠和α细胞株暴露于棕榈酸酯(PA)来确定骨髓间充质干细胞条件培养液(bmMSC-CM)对胰高血糖素分泌的影响。采用酶联免疫吸附试验(EL ISA)检测血浆和培养上清液中胰高血糖素含量。通过Western blotting检测10号染色体缺失的磷酸酶和张力蛋白同源物(PTEN)、AKT和磷酸化AKT(p-AKT)，探讨可能的信号转导途径。结果在体内，bmMSC-CM输注改善了葡萄糖和胰岛素耐量，并对HFD诱导的高血糖和高血糖有保护作用。同时，骨髓间充质干细胞-CM输注可改善高脂饲料诱导的胰岛肥大，减少α和β细胞面积。在体外，α细胞或原代胰岛的胰升糖素分泌持续受到抑制，并伴随着细胞内PTEN表达的降低和AKT信号的恢复。先前的研究和TargetScan数据库表明，miR-181a及其靶标PTEN在改善α细胞功能障碍方面发挥着重要作用。我们观察到miR-181a-5p在BM-MSCs中高表达，而在αTc1-6细胞中低表达。结论MSC来源的miR-181a-5p通过调节PTEN/AKT信号通路抑制α-Tc1-6细胞的胰升糖素分泌，为MSCs治疗T2 DM提供了新的证据。
Backgroundα-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.MethodsIn 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.ResultsIn 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.ConclusionsOur 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.