Extracellular heat shock protein-90alpha: linking hypoxia to skin cell motility and wound healing

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 (hsp90alpha) into the extracellular environment through hypoxia-inducible factor-1alpha (HIF-1alpha). The secreted hsp90alpha in turn executes hypoxia's pro-motility effect. Expression of an activated HIF-1alpha mimicked, whereas expression of an inactive HIF-1alpha or suppression of endogenous HIF-1alpha blocked, hypoxia-induced hsp90alpha secretion and HDF migration. Interestingly, the hypoxia-HIF-1 pathway-induced hsp90alpha secretion required neither changes in the steady-state mRNA level nor in the promoter activity of hsp90alpha. Recombinant hsp90alpha fully duplicated the hypoxia effect on HDFs. Inhibition of extracellular hsp90alpha function completely blocked the hypoxia-HIF-1 pathway-stimulated HDF migration. More intriguingly, topical application of hsp90alpha accelerated wound healing in mice. This study has demonstrated a novel mechanism of hypoxia>HIF-1>hsp90alpha secretion>skin cell migration>wound healing, and identified extracellular hsp90alpha as a potential therapeutic agent for skin wounds.