A fragment of secreted Hsp90α carries properties that enable it to accelerate effectively both acute and diabetic wound healing in mice
Chieh-Fang Cheng, … , David T. Woodley, Wei Li
Chieh-Fang Cheng, … , David T. Woodley, Wei Li
Published October 24, 2011
Citation Information: J Clin Invest. 2011;121(11):4348-4361. https://doi.org/10.1172/JCI46475.
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Research Article Dermatology

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.

Authors

Chieh-Fang Cheng, Divya Sahu, Fred Tsen, Zhengwei Zhao, Jianhua Fan, Rosie Kim, Xinyi Wang, Kathryn O’Brien, Yong Li, Yuting Kuang, Mei Chen, David T. Woodley, Wei Li

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Figure 5

F-5 shortens the time in promoting diabetic wound closure by two-third.

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F-5 shortens the time in promoting diabetic wound closure by two-third. ...
(A) Full-thickness excision wounds (1.2 cm × 1.2 cm) were created on the backs of db/db mice and treated with either placebo (10% CMC gel) or the same gel containing an optimized concentration of F-5 (~1 mM) (n = 3 mice per group, per experiment). The images of 1 out of 4 representative experiments are shown from day 0 to the day of complete closure of F-5–treated wounds. (B) Percentage of the accelerated wound closure on days 0, 5, 10, 14, and 18, with or without F-5 treatment (mean ± SD). *P ≤ 0.05. (C) A single treatment with F-5 on day 0 shortened the wound closure time from 35 days to 14 to 18 days. *P ≤ 0.05, compared with placebo. (D and E) H&E-stained sections of day 14 full-thickness wounds with either (D) placebo or (E) F-5 treatment were analyzed. Independently photographed images with identical magnifications were reconstituted to show the unhealed areas of the wounds. Red dotted lines with arrows indicate unhealed wound space. Yellow dotted lines mark the newly reepithelialized epidermis. The front of newly reepithelialized epidermis was enlarged to show ReT. Note that since the size of the wound biopsy was the same as that of the original wound (1.2 cm × 1.2 cm), we did not expect to visualize any significant portion of the unwounded skin from the H&E staining. Scale bars: 0.25 mm (D and E, center); 0.063 mm (D and E, left and right).