Ginkgo biloba extract promotes osteogenic differentiation of human bone marrow mesenchymal stem cells in a pathway involving Wnt/β-catenin signaling
Ginkgo biloba extract promotes osteogenic differentiation of human bone marrow mesenchymal stem cells in a pathway involving Wnt/β-catenin signaling
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DOI：
10.1016/j.phrs.2015.04.004
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发表时间：
2015-07-01
影响因子：
9.3
通讯作者：
Shi, Lei
中科院分区：
文献类型：
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作者：
Gu, Qiuhan;Chen, Chen;Shi, Lei
人骨髓间充质干细胞（BM-MSCs）具有向成骨细胞分化的潜能，是干细胞治疗骨疾病的一种新的细胞来源。有效诱导人BM-MSCs向成骨细胞分化是实现其治疗潜力的关键。本研究采用传统中药银杏叶提取物（GBE）刺激人骨髓间充质干细胞的增殖和成骨分化。本研究揭示，GBE在25-75 mg/l范围内以剂量依赖性方式改善人BM-MSCs的增殖和成骨，如碱性磷酸酶（ALP）活性和钙含量所示。然而，当浓度为100 mg/l或更高时，这种作用被降低或抑制。GBE对人BM-MSC成骨的剂量依赖性改善进一步通过标记基因骨桥蛋白（OPN）和胶原蛋白I的剂量依赖性上调得到证实。骨保护素（OPG）表达的增加和核因子-κ B配体（RANKL）受体激活剂的最小表达表明GBE也抑制人BM-MSCs的破骨细胞生成。进一步的机制研究表明，在GBE促进成骨过程中，BMP信号通路中的骨形态发生蛋白4（BMP 4）和Runt相关转录因子2（RUNX 2）、Wnt/beta-catenin信号通路中的β-catenin和Cyclin D1的转录水平显著升高。同时，使用信号传导抑制剂的功能丧失测定证实了BMP和Wnt/β-catenin信号传导途径在GBE促进的成骨过程中是不可或缺的，这表明GBE通过上调BMP和Wnt/β-catenin信号传导来改善成骨。本研究提出GBE可用于上调人BM-MSC的成骨分化，用于基于BM-MSC的细胞治疗中的新骨形成，这可能为骨疾病提供有吸引力和有前途的治疗。(c)2015爱思唯尔有限公司版权所有。
Human bone marrow derived mesenchymal stem cells (BM-MSCs) are a novel cell source used in stem cell therapy to treat bone diseases owing to their high potential to differentiate into osteoblasts. Effective induction of osteogenic differentiation from human BM-MSCs is critical to fulfill their therapeutic potential. In this study, Ginkgo biloba extract (GBE), a traditional herbal medicine, was used to stimulate the proliferation and osteogenic differentiation of human BM-MSCs. The present study revealed that GBE improved the proliferation and osteogenesis of human BM-MSCs in a dose-dependent manner in the range 25-75 mg/l, as indicated by alkaline phosphatase (ALP) activity and calcium content. However, such effect was decreased or inhibited at 100 mg/l or higher. The dose-dependent improvement in osteogenesis of human BM-MSCs by GBE was further confirmed by the dose-dependent upregulation of marker genes, osteopontin (OPN) and Collagen I. The increased osteoprotegerin (OPG) expression and minimal expression of receptor activator of nuclear factor-kappa B ligand (RANKL) suggested that GBE also inhibited osteoclastogenesis of human BM-MSCs. Further mechanistic study demonstrated that the transcriptional levels of bone morphogenetic protein 4 (BMP4) and runt-related transcription factor 2 (RUNX2) in the BMP signaling, p-catenin and Cyclin D1 in the Wnt/beta-catenin signaling, increased significantly during GBE-promoted osteogenesis. Meanwhile, loss-of-function assay with the signaling inhibitor(s) confirmed that the BMP and Wnt/beta-catenin signaling pathways were indispensable during the GBE-promoted osteogenesis, suggesting that GBE improved osteogenesis via upregulation of the BMP and Wnt/beta-catenin signaling. The present study proposed GBE to be used to upregulate the osteogenic differentiation of human BM-MSCs for new bone formation in BM-MSC-based cell therapy, which could provide an attractive and promising treatment for bone disorders. (c) 2015 Elsevier Ltd. All rights reserved.