A fragment of secreted Hsp90α carries properties that enable it to accelerate effectively both acute and diabetic wound healing in mice

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.

Review: Multimodal bioactive material approaches for wound healing

“…The Hsp90a gel was shown to increase motility in human keratinocytes, human dermal fibroblasts, and human dermal microvascular endothelial cells, under both healthy conditions and hyperglycemic conditions. 49 Full excisional wounds on a diabetic pig treated with the Hsp90a gel indicated increased re-epithelialization and granulation tissue deposition in comparison to control wounds treated with the industry standard Regranex. 48 Similarly, keratinocytes and dermal cells express the LRP-1 receptor which is implicated in cell motility and Hsp90a signaling.…”

“…48 Similarly, keratinocytes and dermal cells express the LRP-1 receptor which is implicated in cell motility and Hsp90a signaling. 49 Cell motility is largely driven through integrin signaling; therefore, it is necessary to find additional molecules which can promote re-epithelialization by targeting integrins involved in cell motility. 49 …”

“…49 Cell motility is largely driven through integrin signaling; therefore, it is necessary to find additional molecules which can promote re-epithelialization by targeting integrins involved in cell motility. 49 …”

Extracellular Hsp90 (eHsp90) as the Actual Target in Clinical Trials

“…This indicates that the mutations caused a conformational change in the charged linker. It should be pointed out that the epitope of the K41233 antibody is located within the reported F-5 fragment, which retains the full promotility activity of the full-length Hsp90α (Cheng et al, 2011). Therefore, the Ile218 and Leu220 mutations could affect the conformation and function of F-5 as an extracellular promotility factor.…”

The role of membrane-bound heat shock Hsp90 proteins in the migration of tumor cells in vitro and the involvement of cell surface heparan sulfate proteoglycans in protein binding to the plasma membrane

“…Cell Motility plays a key role in many normal physiological processes, including cell migration during gastrulation and tissue regeneration [1]. Cell Motility is usually repressed in many tissues; however, Motility is activated in wound healing (keratinocytes migration to wounded region) or in the process of oncogenic transformation [2,3]. The latter means that the migration of tumor cells is the basis of such pathological processes as tumor cell invasion and metastasis.…”