Basic fibroblast growth factor modifies the hypoxic response of human bone marrow stromal cells by ERK-mediated enhancement of HIF-1α activity
Basic fibroblast growth factor modifies the hypoxic response of human bone marrow stromal cells by ERK-mediated enhancement of HIF-1α activity
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DOI：
10.1016/j.scr.2014.02.007
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发表时间：
2014-05-01
影响因子：
1.2
通讯作者：
Barry, Frank
中科院分区：
文献类型：
--
作者：
Fabian, Zsolt;Ramadurai, Sivaramakrishnan;Barry, Frank
人骨髓基质细胞（hBMSC，也称为骨髓源性间充质干细胞）是用于与各种形式的缺氧相关的人类病理学的细胞治疗的有前途的工具。尽管目前其临床应用的概念包括在标准细胞培养条件下扩增 hBMSC，但促细胞分裂剂驱动的离体扩增对适应低氧环境的影响尚不清楚。在这里，我们提供的数据表明，碱性成纤维细胞生长因子（FGF2）增强了缺氧 hBMSC 中多种缺氧相关适应性基因的诱导。我们发现 FGF2 信号通过与缺氧相似的 ERK 途径传递，该途径也利用相同信号机制的远端元件，包括 hBMSC 中的细胞外信号调节激酶 1/2 (ERK1/2) 和丝裂原激活蛋白激酶激酶 (MEK1/2)。我们发现 FGF2 和缺氧同时激活 ERK1/2 可将激活动力学从振荡转变为持续。激活的 ERK 与稳定的缺氧诱导因子 1 α (HIF-1 α) 共定位，随后其核迁移率降低以及 DNA 结合能力增加，从而导致缺氧适应性基因的上调。我们的研究结果表明 ERK 通路的状态对 hBMSC 对缺氧环境的分子适应具有显着影响。 (C) 2014 年作者。由 Elsevier B.V 出版。这是一篇遵循 CC BY-NC-ND 许可证 (http://creativecommons.org/licenses/by-nc-nd/3.0/) 的开放获取文章。
Human bone marrow stromal cells (hBMSCs, also known as bone marrow-derived mesenchymal stem cells) are promising tools for the cellular therapy of human pathologies related to various forms of hypoxia. Although the current concepts of their clinical use include the expansion of hBMSC in standard cell culture conditions, the effect of the mitogen-driven ex vivo expansion on the adaptation to the hypoxic environment is unknown. Here, we provide data that the basic fibroblast growth factor (FGF2) enhances the induction of a wide range of hypoxia-related adaptive genes in hypoxic hBMSCs. We identified that the FGF2 signal is transmitted by the ERK pathway similar to that of hypoxia that also utilises the distal elements of the same signalling machinery including the extracellular signal-regulated kinase 1/2 (ERK1/2) and mitogen-activated protein kinase kinases (MEK1/2) in hBMSCs. We found that the simultaneous activation of ERK1/2 by FGF2 and hypoxia transforms the activation dynamics from oscillatory into sustained one. Activated ERKs co-localise with stabilised hypoxia inducible factor-1 alpha (HIF-1 alpha) followed by the reduction of its nuclear mobility as well as increased DNA binding capacity leading to the up-regulation of hypoxia-adaptive genes. Our findings indicate that the status of the ERK pathway has significant impacts on the molecular adaptation of hBMSCs to the hypoxic milieu. (C) 2014 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/).