After Conventional Wisdom Has Failed, What Drives Wound Healing?

Abstract

Between 2006 and 2015, the U.S. Food and Drug Administration’s (FDA) overall likelihood of approval (LOA) from Phase I clinical trials for all therapeutic candidates was 9.6%, with the highest LOA in haematology (26.1%) and the lowest in oncology (5.1%). Two critical features attributed to the success of advancing trials were i) targeting driver genes responsible for disease, and ii) use of human disease-relevant animal models during preclinical studies. For decades, conventional wisdom has been that growth factors are the drivers of wound healing, but few have either advanced to clinical applications or proven effective. The purpose of this paper is to explore heat shock protein 90-alpha (Hsp90α)’s role as a potential driver of wound healing and as a possible future therapeutic entity through a review of recent literature, including studies with human disease-relevant animal models. Of the approximately 7,000 gene products generated by a given mammalian cell type, the Hsp90 family of proteins (Hsp90α and Hsp90β) accounts for 2–3% of them. Hsp90β fulfils the role of an intracellular chaperone, but Hsp90α’s intracellular function is surprisingly dispensable. Instead, the abundancy of Hsp90α appears to have been prepared for extracellular purposes. When secreted via exosomes by cells under environmental stress, such as injury, Hsp90α protects cells from hypoxia-induced cell death, reduces local inflammation, and subsequently promotes cell migration to repair the injured tissue. Unlike conventional growth factors, secreted Hsp90α stimulates all major cell types involved in wound healing equally, resists microenvironmental inhibitors like TGFβ and hyperglycaemia, and is highly stable. Inhibition of exosome-mediated Hsp90α secretion, neutralisation of Hsp90α’s ATPase-independent extracellular functions, or interruption of Hsp90α-LRP-1 signalling blocks wound closure in vivo. Topical application of Hsp90α’s therapeutic entity, F-5 (a 115-amino acid peptide), has shown great promise for healing acute burn and diabetic wounds in mice and pigs.