Mechanical stretch induces antioxidant responses and osteogenic differentiation in human mesenchymal stem cells through activation of the AMPK-SIRT1 signaling pathway.
Mechanical stretch induces antioxidant responses and osteogenic differentiation in human mesenchymal stem cells through activation of the AMPK-SIRT1 signaling pathway.
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机械拉伸通过激活 AMPK-SIRT1 信号通路诱导人间充质干细胞的抗氧化反应和成骨分化。
DOI：
10.1016/j.freeradbiomed.2018.08.001
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发表时间：
2018-10
影响因子：
7.4
通讯作者：
Luo ZP
中科院分区：
文献类型：
--
作者：
Chen X;Yan J;He F;Zhong D;Yang H;Pei M;Luo ZP
间充质干细胞（MSCs）是一种很有前景的再生医学细胞来源。越来越多的证据表明，机械刺激对它们的谱系特异性分化至关重要。然而，机械负荷对MSCs氧化还原平衡和细胞内抗氧化系统的影响尚不清楚。在这项研究中，人骨髓来源的MSCs （BM-MSCs）在2.5%、5%和10%的幅度下进行循环拉伸。观察细胞增殖、细胞内活性氧（ROS）、抗氧化酶的表达和成骨分化。提取RNA并进行DNA芯片分析。Sirtinol和化合物C被用于研究沉默信息调节因子1型（SIRT1）和amp活化蛋白激酶（AMPK）的潜在机制。我们的研究结果表明，适当程度的机械拉伸增加了细胞增殖，上调了细胞外基质组织，下调了基质分解。拉伸3 d后，BM-MSCs细胞内ROS减少，但抗氧化酶水平，尤其是超氧化物歧化酶1 （SOD1）水平上调。拉伸5%而不是拉伸10%可促进成骨，这可以通过增加基质矿化和成骨标记基因表达来证明。机械拉伸增强了SIRT1的表达和AMPK的磷酸化；然而，SIRT1或AMPK的抑制消除了拉伸诱导的对BM-MSCs的抗氧化作用，抑制了拉伸介导的成骨分化。我们的研究结果表明，机械拉伸诱导了抗氧化反应，减弱了细胞内ROS，并促进了BM-MSCs的成骨。拉伸诱导的抗氧化作用是通过激活AMPK-SIRT1信号通路实现的。我们的研究结果表明，适当的机械刺激可以提高骨髓间充质干细胞的抗氧化功能，有利于骨再生。
Mesenchymal stem cells (MSCs) are promising cell sources for regenerative medicine. Growing evidence has indicated that mechanical stimuli are crucial for their lineage-specific differentiation. However, the effect of mechanical loading on redox balance and the intracellular antioxidant system in MSCs was unknown. In this study, human bone marrow-derived MSCs (BM-MSCs) were subjected to cyclic stretch at the magnitude of 2.5%, 5%, and 10%. Cell proliferation, intracellular reactive oxygen species (ROS), expression of antioxidant enzymes, and osteogenic differentiation were evaluated. RNA was extracted and subjected to DNA microarray analysis. Sirtinol and compound C were used to investigate the underlying mechanisms involved silent information regulator type 1 (SIRT1) and AMP-activated protein kinase (AMPK). Our results showed that mechanical stretch at appropriate magnitudes increased cell proliferation, up-regulated extracellular matrix organization, and down-regulated matrix disassembly. After 3 days of stretch, intracellular ROS in BM-MSCs were decreased but the levels of antioxidant enzymes, especially superoxide dismutase 1 (SOD1), were up-regulated. Osteogenesis was improved by 5% stretch rather than 10% stretch, as evidenced by increased matrix mineralization and osteogenic marker gene expression. The expression of SIRT1 and phosphorylation of AMPK were enhanced by mechanical stretch; however, inhibition of SIRT1 or AMPK abrogated the stretch-induced antioxidant effect on BM-MSCs and inhibited the stretch-mediated osteogenic differentiation. Our findings reveal that mechanical stretch induced antioxidant responses, attenuated intracellular ROS, and improved osteogenesis of BM-MSCs. The stretch-induced antioxidant effect was through activation of the AMPK-SIRT1 signaling pathway. Our findings demonstrated that appropriate mechanical stimulation can improve MSC antioxidant functions and benefit bone regeneration.
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