Epidermal growth factor can signal via β-catenin to control proliferation of mesenchymal stem cells independently of canonical Wnt signalling.
Epidermal growth factor can signal via β-catenin to control proliferation of mesenchymal stem cells independently of canonical Wnt signalling.
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DOI：
10.1016/j.cellsig.2018.09.021
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发表时间：
2019-01
影响因子：
4.8
通讯作者：
Genever P
中科院分区：
文献类型：
--
作者：
Knight C;James S;Kuntin D;Fox J;Newling K;Hollings S;Pennock R;Genever P
骨髓间充质干细胞/基质细胞(MSCs)通过对有丝分裂刺激的扩增和分化为骨系来维持骨的动态平衡和修复。能够精确控制MSC功能的信号机制仍然不清楚。在这里，我们报告，通过最初检测单个MSC克隆的信号通路表达谱的差异，我们在原代人MSCs中发现了一种先前未被识别的受表皮生长因子(EGF)调控的信号机制。我们证明，表皮生长因子能够激活β-连环蛋白，这是典型的Wnt信号通路的关键组成部分。表皮生长因子能够诱导人骨髓间充质干细胞β-连环蛋白的核转位，但不能促进WNT靶基因的表达或T细胞因子的活性。使用有效的实验设计统计分析，在不同组合和浓度的表皮生长因子和Wnt配体的情况下，我们能够证实表皮生长因子不影响骨髓间充质干细胞中Wnt/β-catenin通路。我们发现，表皮生长因子对骨髓间充质干细胞的作用是时间上的调节，以启动早期的经典的表皮生长因子信号机制(例如，通过丝裂原激活的蛋白激酶)，延迟激活β-连环蛋白。通过测序，我们发现了完全受表皮生长因子/β-连环蛋白途径调控的基因集合，这些基因不同于经典的表皮生长因子调控基因。然而，经典的表皮生长因子基因靶点亚群受到表皮生长因子/β-连环蛋白激活的显著影响。这些信号通路协同作用，通过减轻经典的EGF信号对细胞周期通路的抑制，使EGF介导的MSCs增殖成为可能。表皮生长因子(EGF)控制间充质干细胞(MSC)的增殖。表皮生长因子在MSCs中通过β-连环蛋白表达，而在相关的成纤维细胞中不表达。经典的表皮生长因子和表皮生长因子/β-连环蛋白协同调节骨髓间充质干细胞中不同的基因集。表皮生长因子/β-连环蛋白通过减轻细胞周期抑制而促进骨髓间充质干细胞增殖。
Bone marrow mesenchymal stem/stromal cells (MSCs) maintain bone homeostasis and repair through the ability to expand in response to mitotic stimuli and differentiate into skeletal lineages. Signalling mechanisms that enable precise control of MSC function remain unclear. Here we report that by initially examining differences in signalling pathway expression profiles of individual MSC clones, we identified a previously unrecognised signalling mechanism regulated by epidermal growth factor (EGF) in primary human MSCs. We demonstrate that EGF is able to activate β-catenin, a key component of the canonical Wnt signalling pathway. EGF is able to induce nuclear translocation of β-catenin in human MSCs but does not drive expression of Wnt target genes or T cell factor (TCF) activity in MSC reporter cell lines. Using an efficient Design of Experiments (DoE) statistical analysis, with different combinations and concentrations of EGF and Wnt ligands, we were able to confirm that EGF does not influence the Wnt/β-catenin pathway in MSCs. We show that the effects of EGF on MSCs are temporally regulated to initiate early “classical” EGF signalling mechanisms (e.g via mitogen activated protein kinase) with delayed activation of β-catenin. By RNA-sequencing, we identified gene sets that were exclusively regulated by the EGF/β-catenin pathway, which were distinct from classical EGF-regulated genes. However, subsets of classical EGF gene targets were significantly influenced by EGF/β-catenin activation. These signalling pathways cooperate to enable EGF-mediated proliferation of MSCs by alleviating the suppression of cell cycle pathways induced by classical EGF signalling. Epidermal growth factor (EGF) controls mesenchymal stem cell (MSC) proliferation. EGF signals through β-catenin in MSCs but not in related fibroblastic cells. Classical EGF and EGF/β-catenin cooperatively regulate distinct gene sets in MSCs. EGF/β-catenin enables MSC proliferation by alleviating cell cycle suppression.
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影响因子：
5.9
作者：
James, Sally;Fox, James;Afsari, Farinaz;Lee, Jennifer;Clough, Sally;Knight, Charlotte;Ashmore, James;Ashton, Peter;Preham, Olivier;Hoogduijn, Martin;Ponzoni, Raquel De Almeida Rocha;Hancock, Y.;Coles, Mark;Genever, Paul
通讯作者：
Genever, Paul
影响因子：
6.2
作者：
Chen, Jianquan;Long, Fanxin
通讯作者：
Long, Fanxin
影响因子：
64.5
作者：
Gong, YQ;Slee, RB;Warman, ML
通讯作者：
Warman, ML
影响因子：
5.3
作者：
Kim, Chang-Hoon;Neiswender, Hannah;Mei, Lin
通讯作者：
Mei, Lin
DOI：
10.1073/pnas.0914360107
发表时间：
2010-03-02
影响因子：
11.1
作者：
Krause, Ulf;Harris, Sean;Gregory, Carl A.
通讯作者：
Gregory, Carl A.