Hanako Yamaoka1, Hideaki Sumiyoshi2, Kiyoshi Higashi3, Sachie Nakao2, Kaori Minakawa4, Kayo Sumida3, Koichi Saito3, Norihiro Ikoma5, Tomotaka Mabuchi5, Akira Ozawa5, Yutaka Inagaki6. 1. Department of Dermatology, Tokai University School of Medicine, Isehara, Japan; Center for Matrix Biology and Medicine, Graduate School of Medicine, Tokai University, Isehara, Japan. 2. 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. 3. Environmental Health Science Laboratory, Sumitomo Chemical Co. Ltd., Osaka, Japan. 4. Department of Regenerative Medicine, Tokai University School of Medicine, Isehara, Japan; Institute of Medical Sciences, Tokai University, Isehara, Japan. 5. Department of Dermatology, Tokai University School of Medicine, Isehara, Japan. 6. 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.
Abstract
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. CONCLUSION: 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.
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. CONCLUSION: 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.
Authors: Matthew D Cheeseman; Nicola E A Chessum; Carl S Rye; A Elisa Pasqua; Michael J Tucker; Birgit Wilding; Lindsay E Evans; Susan Lepri; Meirion Richards; Swee Y Sharp; Salyha Ali; Martin Rowlands; Lisa O'Fee; Asadh Miah; Angela Hayes; Alan T Henley; Marissa Powers; Robert Te Poele; Emmanuel De Billy; Loredana Pellegrino; Florence Raynaud; Rosemary Burke; Rob L M van Montfort; Suzanne A Eccles; Paul Workman; Keith Jones Journal: J Med Chem Date: 2016-12-22 Impact factor: 7.446
Authors: Francisco Perez-Dominguez; Diego Carrillo-Beltrán; Rancés Blanco; Juan P Muñoz; Grettell León-Cruz; Alejandro H Corvalan; Ulises Urzúa; Gloria M Calaf; Francisco Aguayo Journal: Biology (Basel) Date: 2021-02-04