A novel small compound accelerates dermal wound healing by modifying infiltration, proliferation and migration of distinct cellular components in mice.
BACKGROUND
Impaired wound healing in skin ulcer is one of the major medical issues in the aged society. Wound healing is a complex process orchestrated by a number of humoral factors and cellular components. TGF-β is known to stimulate collagen production in dermal fibroblasts while inhibiting proliferation of epidermal keratinocyte. A screening of small compounds that suppress type I collagen production in fibroblasts has identified HSc025 that antagonizes the TGF-β/Smad signal.


OBJECTIVE
We examined the effects of HSc025 on dermal wound healing and elucidated the underlying mechanisms.


METHODS
Effects of HSc025 on the wound closure process were evaluated in a murine full-thickness excisional wound healing model. Cell proliferation and migration were estimated using primary cultures of human keratinocytes and fibroblasts. Comprehensive analyses of gene expression profiles were performed using untreated and HSc025-treated fibroblasts.


RESULTS
Oral HSc025 administration suppressed macrophage infiltration and accelerated wound closure as early as at day 2 after the dermal excision. Treatment of cultured keratinocytes with HSc025 counteracted the inhibitory effects of TGF-β on cell proliferation and migration. On the other hand, HSc025 stimulated migration, but not proliferation, of dermal fibroblasts independently of TGF-β. Experiments using an artificial dermis graft revealed that HSc025 stimulated migration of collagen-producing cells into the graft tissue. A cDNA microarray analysis of untreated and HSc025-treated fibroblasts identified pirin as a critical mediator accelerating fibroblast migration.


CONCLUSIONS
HSc025 accelerates wound healing by modifying infiltration, proliferation and migration of distinct cellular components, which provides a novel insight into the therapy for intractable skin ulcer.
Department of Dermatology, Tokai University School of Medicine, Isehara, Japan; Center for Matrix Biology and Medicine, Graduate School of Medicine, Tokai University, Isehara, Japan.
Hanako
H
Yamaoka
Department of Regenerative Medicine, Tokai University School of Medicine, Isehara, Japan; Center for Matrix Biology and Medicine, Graduate School of Medicine, Tokai University, Isehara, Japan; Institute of Medical Sciences, Tokai University, Isehara, Japan.
Hideaki
H
Sumiyoshi
Environmental Health Science Laboratory, Sumitomo Chemical Co. Ltd., Osaka, Japan.
Kiyoshi
K
Higashi
Department of Regenerative Medicine, Tokai University School of Medicine, Isehara, Japan; Center for Matrix Biology and Medicine, Graduate School of Medicine, Tokai University, Isehara, Japan; Institute of Medical Sciences, Tokai University, Isehara, Japan.
Sachie
S
Nakao
Department of Regenerative Medicine, Tokai University School of Medicine, Isehara, Japan; Institute of Medical Sciences, Tokai University, Isehara, Japan.
Kaori
K
Minakawa
Environmental Health Science Laboratory, Sumitomo Chemical Co. Ltd., Osaka, Japan.
Kayo
K
Sumida
Environmental Health Science Laboratory, Sumitomo Chemical Co. Ltd., Osaka, Japan.
Koichi
K
Saito
Department of Dermatology, Tokai University School of Medicine, Isehara, Japan.
Norihiro
N
Ikoma
Department of Dermatology, Tokai University School of Medicine, Isehara, Japan.
Tomotaka
T
Mabuchi
Department of Dermatology, Tokai University School of Medicine, Isehara, Japan.
Akira
A
Ozawa
Department of Regenerative Medicine, Tokai University School of Medicine, Isehara, Japan; Center for Matrix Biology and Medicine, Graduate School of Medicine, Tokai University, Isehara, Japan; Institute of Medical Sciences, Tokai University, Isehara, Japan; CREST, Japan Science Technology, Tokyo, Japan. Electronic address: yutakai@is.icc.u-tokai.ac.jp.
Yutaka
Y
Inagaki
D000466:Alkadienes / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D024042:Collagen Type I / Q000235:genetics / Q000378:metabolism; D049308:Dioxygenases; D004353:Drug Evaluation, Preclinical; D005260:Female; D005347:Fibroblasts / Q000187:drug effects; D006097:Granulation Tissue / Q000166:cytology; D006801:Humans; D015603:Keratinocytes / Q000187:drug effects; D051379:Mice; D009687:Nuclear Proteins / Q000378:metabolism; D012883:Skin Ulcer / Q000188:drug therapy*; D016212:Transforming Growth Factor beta; D014945:Wound Healing / Q000187:drug effects*
D000466:Alkadienes; D002352:Carrier Proteins; D024042:Collagen Type I; C546007:HSc025; D009687:Nuclear Proteins; D016212:Transforming Growth Factor beta; D049308:Dioxygenases; C105340:PIR protein, human
Artificial dermis graft; Pirin; TGF-β/Smad3 signal; Wound healing