Lithium Stimulates HumanBone Marrow-Derived Mesenchymal Stem Cell Proliferation Through GSK-3-beta-DependentBeta-catenin/Wnt Pathway Activation
Lithium Stimulates HumanBone Marrow-Derived Mesenchymal Stem Cell Proliferation Through GSK-3-beta-DependentBeta-catenin/Wnt Pathway Activation
复制标题
锂通过 GSK-3-β-依赖性 Beta-catenin/Wnt 通路激活刺激人骨髓源性间充质干细胞增殖
DOI：
10.1111/febs.13081
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发表时间：
2014
期刊：
影响因子：
5.4
通讯作者：
Zhang Changqing
中科院分区：
文献类型：
--
作者：
Zhu Zhenzhong;Yin Junhui;Guan Junjie;Hu Bin;Niu Xin;Jin Dongxu;Wang Yang;Zhang Changqing
间充质干细胞（Mesenchymal stem cells，MSCs）是一种多能干细胞，已广泛应用于细胞移植治疗。MSC的使用需要体外扩增以实现其再生能力。因此，MSC的增殖能力是决定MSC治疗效果的关键因素之一。在本研究中，我们首次证明锂（一种众所周知的抗抑郁药）在体外可逆地促进人骨髓源性MSC的增殖。用5 mm锂处理的MSC比未处理的细胞增殖更快，而不经历凋亡。锂可增加S期细胞比例及cyclin D1表达。机制研究表明，这些作用依赖于糖原合成酶激酶3β（GSK-3β）介导的经典Wnt途径的激活。锂诱导Ser 9磷酸化，导致GSK-3β活性、β-连环蛋白蓄积和Wnt通路激活受到抑制。使用特异性GSK-3β抑制剂SB 216763或siRNA介导的GSK-3β抑制产生的效应与锂诱导的效应相似。相比之下，槲皮素（β-catenin/TCF通路的抑制剂）或siRNA介导的β-catenin敲低均消除了锂的增殖作用，表明锂通过GSK-3β依赖性β-catenin/Wnt通路刺激MSC增殖。总的来说，这些研究阐明了锂的新作用，这不仅可以提供一种简单有效的方法来加强MSC移植治疗的疗效，而且还阐明了锂在治疗β-catenin/Wnt通路抑制引起的某些疾病中的临床应用。
Mesenchymal stem cells (MSCs) are multipotent cells that have been widely used in cell based transplantation therapy. The use of MSCs requires in vitro expansion in order to fulfill their regenerative capacity. Therefore the proliferative ability of MSCs is one of the key factors which determine MSC therapeutic efficacy. In the present study, we showed for the first time that lithium, a well‐known antidepressant, reversibly promoted the proliferation of human bone marrow derived MSCs in vitro. MSCs treated with 5 mm lithium proliferated more rapidly than untreated cells without undergoing apoptosis. Lithium increased the proportion of cells in S phase as well as cyclin D1 expression. Mechanistic studies revealed that these effects were dependent upon the activation of the glycogen synthase kinase 3β (GSK‐3β) mediated canonical Wnt pathway. Lithium induced Ser9 phosphorylation, which results in the inhibition of GSK‐3β activity, β‐catenin accumulation and Wnt pathway activation. Utilizing a specific GSK‐3β inhibitor SB216763 or siRNA‐mediated inhibition of GSK‐3β produced effects similar to those induced by lithium. In contrast, either quercetin, an inhibitor of the β‐catenin/TCF pathway, or siRNA‐mediated knockdown of β‐catenin abolished the proliferative effect of lithium, suggesting that lithium stimulates MSC proliferation via the GSK‐3β‐dependent β‐catenin/Wnt pathway. Collectively, these studies elucidate a novel role of lithium, which may not only provide a simple and effective way to strengthen MSC transplantation therapy efficacy but also shed light on lithium's clinical application for the treatment of certain disorders resulting from β‐catenin/Wnt pathway suppression.