Extracellular heat shock protein-90α:: linking hypoxia to skin cell motility and wound healing
Extracellular heat shock protein-90α:: linking hypoxia to skin cell motility and wound healing
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DOI：
10.1038/sj.emboj.7601579
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发表时间：
2007-03-07
期刊：
影响因子：
11.4
通讯作者：
Woodley, David T.
中科院分区：
文献类型：
--
作者：
Li, Wei;Li, Yong;Woodley, David T.
缺氧是受伤皮肤中的微环境应激，在那里它通过促进细胞运动来支持伤口愈合。缺氧作用的机制仍然是推测性的。在这里，我们提供的证据表明，缺氧促进人类皮肤成纤维细胞（HDF）迁移诱导分泌热休克蛋白90 α（HSP 90 α）进入细胞外环境，通过缺氧诱导因子-1 α（HIF-1 α）。分泌的热休克蛋白90 α反过来执行缺氧的促运动作用。模拟活化的HIF-1 α的表达，而无活性的HIF-1 α的表达或内源性HIF-1 α的抑制阻断缺氧诱导的hsp 90 α分泌和HDF迁移。有趣的是，缺氧-HIF-1途径诱导的hsp 90 a分泌既不需要改变稳态mRNA水平，也不需要改变hsp 90 a的启动子活性。重组hsp 90 a完全复制了对HDFs的缺氧作用。细胞外hsp 90 a功能的抑制完全阻断了缺氧-HIF-1途径刺激的HDF迁移。更有趣的是，局部应用hsp 90 a加速了小鼠伤口愈合。这项研究证明了缺氧> HIF-1 > hsp 90 α分泌>皮肤细胞迁移>伤口愈合的新机制，并确定细胞外hsp 90 α作为皮肤伤口的潜在治疗剂。
Hypoxia is a microenvironmental stress in wounded skin, where it supports wound healing by promoting cell motility. The mechanism of the hypoxia action remained speculative. Here, we provide evidence that hypoxia promotes human dermal fibroblast (HDF) migration by inducing secretion of heat shock protein-90alpha (hsp90 alpha) into the extracellular environment through hypoxia-inducible factor-1alpha (HIF-1 alpha). The secreted hsp90 alpha in turn executes hypoxia's pro-motility effect. Expression of an activated HIF-1 alpha mimicked, whereas expression of an inactive HIF-1 alpha or suppression of endogenous HIF-1 alpha blocked, hypoxia- induced hsp90a secretion and HDF migration. Interestingly, the hypoxia-HIF-1 pathway-induced hsp90a secretion required neither changes in the steady-state mRNA level nor in the promoter activity of hsp90a. Recombinant hsp90a fully duplicated the hypoxia effect on HDFs. Inhibition of extracellular hsp90a function completely blocked the hypoxia-HIF-1 pathway-stimulated HDF migration. More intriguingly, topical application of hsp90a accelerated wound healing in mice. This study has demonstrated a novel mechanism of hypoxia > HIF-1 > hsp90 alpha secretion > skin cell migration > wound healing, and identified extracellular hsp90 alpha as a potential therapeutic agent for skin wounds.