A fragment of secreted Hsp90α carries properties that enable it to accelerate effectively both acute and diabetic wound healing in mice
Open Access
- 1 November 2011
- journal article
- Published by American Society for Clinical Investigation in JCI Insight
- Vol. 121 (11), 4348-4361
- https://doi.org/10.1172/jci46475
Abstract
Wounds that fail to heal in a timely manner, for example, diabetic foot ulcers, pose a health, economic, and social problem worldwide. For decades, conventional wisdom has pointed to growth factors as the main driving force of wound healing; thus, growth factors have become the center of therapeutic developments. To date, becaplermin (recombinant human PDGF-BB) is the only US FDA-approved growth factor therapy, and it shows modest efficacy, is costly, and has the potential to cause cancer in patients. Other molecules that drive wound healing have therefore been sought. In this context, it has been noticed that wounds do not heal without the participation of secreted Hsp90α. Here, we report that a 115-aa fragment of secreted Hsp90α (F-5) acts as an unconventional wound healing agent in mice. Topical application of F-5 peptide promoted acute and diabetic wound closure in mice far more effectively than did PDGF-BB. The stronger effect of F-5 was due to 3 properties not held by conventional growth factors: its ability to recruit both epidermal and dermal cells; the fact that its ability to promote dermal cell migration was not inhibited by TGF-β; and its ability to override the inhibitory effects of hyperglycemia on cell migration in diabetes. The discovery of F-5 challenges the long-standing paradigm of wound healing factors and reveals a potentially more effective and safer agent for healing acute and diabetic wounds.Keywords
This publication has 63 references indexed in Scilit:
- Human skin wounds: A major and snowballing threat to public health and the economyWound Repair and Regeneration, 2009
- Participation of the lipoprotein receptor LRP1 in hypoxia-HSP90α autocrine signaling to promote keratinocyte migrationJournal of Cell Science, 2009
- Stabilization of HIF-1α is critical to improve wound healing in diabetic miceProceedings of the National Academy of Sciences of the United States of America, 2008
- Transforming Growth Factor α (TGFα)-Stimulated Secretion of HSP90α: Using the Receptor LRP-1/CD91 To Promote Human Skin Cell Migration against a TGFβ-Rich Environment during Wound HealingMolecular and Cellular Biology, 2008
- Intravenously Injected Human Fibroblasts Home to Skin Wounds, Deliver Type VII Collagen, and Promote Wound HealingMolecular Therapy, 2007
- Extracellular heat shock protein-90α: linking hypoxia to skin cell motility and wound healingThe EMBO Journal, 2007
- Signals that Initiate, Augment, and Provide Directionality for Human Keratinocyte MotilityJournal of Investigative Dermatology, 2004
- Becaplermin: recombinant platelet derived growth factor, a new treatment for healing diabetic foot ulcersExpert Opinion on Biological Therapy, 2002
- Cutaneous Wound HealingThe New England Journal of Medicine, 1999
- Enhancement of Wound Healing by Topical Treatment with Epidermal Growth FactorThe New England Journal of Medicine, 1989