Fibroblast growth factor 2 (Fgf2) inhibits differentiation of mesenchymal stem cells by inducing Twist2 and Spry4, blocking extracellular regulated kinase activation, and altering Fgf receptor expression levels.
Fibroblast growth factor 2 (Fgf2) inhibits differentiation of mesenchymal stem cells by inducing Twist2 and Spry4, blocking extracellular regulated kinase activation, and altering Fgf receptor expression levels.
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DOI：
10.1002/stem.661
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发表时间：
2011-07
期刊：
影响因子：
5.2
通讯作者：
Phinney, Donald G.
中科院分区：
文献类型：
--
作者：
Lai, Wen-Tzu;Krishnappa, Veena;Phinney, Donald G.
关键词：
已知间充质干细胞 (MSC) 可以分化为结缔组织谱系，但维持细胞处于未分化状态的细胞内信号传导途径在很大程度上仍未被探索。之前我们报道过成纤维细胞生长因子 2 (Fgf2) 可逆地抑制原代小鼠 MSC 的多谱系分化，现在我们发现了一种独特的信号蛋白，这些信号蛋白受这种有丝分裂原动态调节，其表达水平与细胞分化的抑制密切相关。 Fgf2 选择性诱导 Twist2 和 Sprouty4 (Spry4) 的表达，并抑制可溶性卷曲相关受体 2 (Sfrp2)、runt 相关转录因子 2 (Runx2) 和过氧化物酶体增殖激活受体 γ (Pparg) 的表达。相比之下，Wnt3a 诱导 Twist 的表达，但不诱导 Twist2 或 Spry4 的表达，并且骨形态发生蛋白 2 (Bmp2) 未能改变所有三个基因的表达。此外，用 Fgf2 预处理 MSC 会延迟细胞外调节激酶 1 和 2 (Erk1/2) 磷酸化，并在骨诱导过程中抑制骨特异性基因表达。或者，Wnt3a 预处理没有效果，而 BMP2 预处理增强了 ERk1/2 激活和骨特异性基因表达。 Fgf2 还诱导 MSC 中 Fgfr1 和 4 的表达并抑制 Fgfr2 和 3 的表达，而 Wnt3a 和 Bmp2 则具有相反的作用。最后，免疫染色显示 Twist 和 Spry4 在 MSC 中共表达，并且 Fgf2 处理以与其作用模式一致的方式改变了它们的亚细胞分布。总的来说，这些研究表明 Fgf2 对小鼠 MSC 分化的抑制与 Twist2 和 Spry4 的上调以及 Erk1/2 激活的抑制密切相关。
Mesenchymal stem cells (MSCs) are known to differentiate into connective tissue lineages but intracellular signaling pathways that maintain cells in an undifferentiated state remain largely unexplored. Previously we reported that fibroblast growth factor 2 (Fgf2) reversibly inhibited multi-lineage differentiation of primary mouse MSCs and now identify a unique compliment of signaling proteins that are dynamically regulated by this mitogen and whose expression levels are strongly correlated with inhibition of cell differentiation. Fgf2 selectively induced expression of Twist2 and Sprouty4 (Spry4) and repressed expression of soluble frizzled related receptor 2 (Sfrp2), runt-related transcription factor 2 (Runx2), and peroxisome proliferation activated receptor gamma (Pparg). In contrast, Wnt3a induced expression of Twist but not Twist2 or Spry4 and bone morphogenetic protein 2 (Bmp2) failed to alter expression of all three genes. Moreover, pre-treatment of MSCs with Fgf2 delayed extracellular regulated kinase 1 and 2 (Erk1/2) phosphorylation and repressed bone-specific gene expression during an osteo-induction time course. Alternatively, pre-treatment with Wnt3a had no effect whereas BMP2 pretreatment augmented ERk1/2 activation and bone-specific gene expression. Fgf2 also induced expression of Fgfr1 and 4 and repressed Fgfr2 and 3 expression in MSCs, whereas Wnt3a and Bmp2 had the opposite effect. Finally, immuno-staining revealed that Twist and Spry4 were co-expressed in MSCs and that Fgf2 treatment altered their sub cellular distribution in a manner consistent with their mode of action. Collectively, these studies demonstrate that inhibition of mouse MSC differentiation by Fgf2 is strongly correlated with up regulation of Twist2 and Spry4 and suppression of Erk1/2 activation.
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