Icariin Protects Bone Marrow Mesenchymal Stem Cells Against Iron Overload Induced Dysfunction Through Mitochondrial Fusion and Fission, PI3K/AKT/mTOR and MAPK Pathways
Icariin Protects Bone Marrow Mesenchymal Stem Cells Against Iron Overload Induced Dysfunction Through Mitochondrial Fusion and Fission, PI3K/AKT/mTOR and MAPK Pathways
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淫羊藿苷通过线粒体融合和裂变、PI3K/AKT/mTOR 和 MAPK 途径保护骨髓间充质干细胞免受铁过载引起的功能障碍
DOI：
10.3389/fphar.2019.00163
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发表时间：
2019-02-28
影响因子：
5.6
通讯作者：
Ye, Yaping
中科院分区：
文献类型：
--
作者：
Yao, Xudong;Jing, Xingzhi;Ye, Yaping
铁超载导致骨髓间充质干细胞（BMSCs）损伤，但其确切机制尚不清楚。淫羊藿苷是从淫羊藿中分离得到的黄酮苷类化合物中的一种主要活性单体，对氧化应激诱导的细胞凋亡具有保护作用。本研究旨在探讨淫羊藿苷对铁超载诱导的骨髓间充质干细胞功能障碍的保护作用及其机制。本研究发现，100 μ M枸橼酸铁铵（FAC）诱导的铁超载可引起BMSCs凋亡，促进caspase-3和BAX蛋白表达，抑制Bcl-2蛋白表达，淫羊藿苷可明显减弱这种作用。此外，铁超载诱导线粒体膜电位（MMP），活性氧（ROS）的产生和线粒体融合/分裂的抑制显着的去极化，这些影响也被淫羊藿苷治疗减弱。同时发现100 μ M FAC诱导的铁超载显著抑制了线粒体分裂蛋白FIS 1和融合蛋白MFN2的表达，抑制了DRP 1和细胞色素C蛋白从细胞质向线粒体的移位。1 μ M的淫羊藿苷能促进线粒体分裂蛋白FIS 1和融合蛋白MFN2的表达，增加细胞色素C和细胞色素P1蛋白从细胞质向线粒体的转运。此外，成骨分化和增殖的骨髓基质细胞显着抑制铁超载，但淫羊藿苷治疗挽救成骨分化和增殖的骨髓基质细胞。进一步的研究表明，淫羊藿苷可减弱铁超载引起的PI3K/AKT/mTOR通路的失活以及ERK 1/2和JNK通路的激活。总之，我们的研究表明，淫羊藿苷能够保护铁超载诱导的BMSCs功能障碍。这些作用可能与调节线粒体融合和分裂、激活PI3K/AKT/mTOR通路以及抑制ERK 1/2和JNK通路有关。
Iron overload has been reported to contribute to bone marrow mesenchymal stem cells (BMSCs) damage, but the precise mechanism still remains elusive. Icariin, a major bioactive monomer belonging to flavonoid glucosides isolated from Herba Epimedii, has been shown to protect cells from oxidative stress induced apoptosis. The aim of this study was to investigate whether icariin protected against iron overload induced dysfunction of BMSCs and its underlying mechanism. In this study, we found that iron overload induced by 100 μM ferric ammonium citrate (FAC) caused apoptosis of BMSCs, promoted cleaved caspase-3 and BAX protein expressions while inhibited Bcl-2 protein expression, which effects were significantly attenuated by icariin treatment. In addition, iron overload induced significant depolarization of mitochondrial membrane potential (MMP), reactive oxygen species (ROS) generation and inhibition of mitochondrial fusion/fission, which effects were also attenuated by icariin treatment. Meanwhile, we found that iron overload induced by 100 μM FAC significantly inhibited mitochondrial fission protein FIS1 and fusion protein MFN2 expressions, inhibited DRP1 and Cytochrome C protein translocation from the cytoplasm to mitochondria. Icariin at concentration of 1 μM was able to promote mitochondrial fission protein FIS1 and fusion protein MFN2 expressions, and increase DRP1 and cytochrome C protein translocation from the cytoplasm to mitochondria. Further, osteogenic differentiation and proliferation of BMSCs was significantly inhibited by iron overload, but icariin treatment rescued both osteogenic differentiation and proliferation of BMSCs. Further studies showed that icariin attenuated iron overload induced inactivation of the PI3K/AKT/mTOR pathway and activation of the ERK1/2 and JNK pathways. In summary, our study indicated that icariin was able to protect against iron overload induced dysfunction of BMSCs. These effects were potentially related to the modulation of mitochondrial fusion and fission, activation of the PI3K/AKT/mTOR pathway and inhibition of ERK1/2 and JNK pathways.