Extracellular heat shock protein-90α: Linking hypoxia to skin cell motility and wound healing

Abstract

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 (hsp90α) into the extracellular environment through hypoxia-inducible factor-1alpha (HIF-1α). The secreted hsp90α in turn executes hypoxia's pro-motility effect. Expression of an activated HIF-1α mimicked, whereas expression of an inactive HIF-1α or suppression of endogenous HIF-1α blocked, hypoxia-induced hsp90α secretion and HDF migration. Interestingly, the hypoxia-HIF-1 pathway-induced hsp90α secretion required neither changes in the steady-state mRNA level nor in the promoter activity of hsp90α. Recombinant hsp90α fully duplicated the hypoxia effect on HDFs. Inhibition of extracellular hsp90α function completely blocked the hypoxia-HIF-1 pathway-stimulated HDF migration. More intriguingly, topical application of hsp90α accelerated wound healing in mice. This study has demonstrated a novel mechanism of hypoxia>HIF- 1>hsp90α secretion>skin cell migration>wound healing, and identified extracellular hsp90α as a potential therapeutic agent for skin wounds. © 2007 European Molecular Biology Organization | All Rights Reserved.