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First published online May 28, 2005
doi: 10.1242/10.1242/jcs.02346

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Heparin-binding EGF-like growth factor accelerates keratinocyte migration and skin wound healing

Yuji Shirakata^1,*,, Rina Kimura^2,*, Daisuke Nanba³, Ryo Iwamoto², Sho Tokumaru¹, Chie Morimoto³, Koichi Yokota⁴, Masanori Nakamura⁴, Koji Sayama¹, Eisuke Mekada², Shigeki Higashiyama³ and Koji Hashimoto¹

¹ Department of Dermatology, Ehime University School of Medicine, Ehime 791-0295, Japan
² Research Institute for Microbial Diseases, Osaka University, Osaka 565-0871, Japan
³ Biochemistry and Molecular Genetics, Ehime University School of Medicine, Ehime 791-0295, Japan
⁴ Carna Biosciences Incorporated, Kobe, Hyogo 650-0047, Japan

Author for correspondence (e-mail: shirakat{at}m.ehime-u.ac.jp)

Accepted 14 February 2005

Members of the epidermal growth factor (EGF) family are the most important growth factors involved in epithelialization during cutaneous wound healing. Heparin-binding EGF-like growth factor (HB-EGF), a member of the EGF family, is thought to play an important role in skin wound healing. To investigate the in vivo function of HB-EGF in skin wound healing, we generated keratinocyte-specific HB-EGF-deficient mice using Cre/loxP technology in combination with the keratin 5 promoter. Studies of wound healing revealed that wound closure was markedly impaired in keratinocyte-specific HB-EGF-deficient mice. HB-EGF mRNA was upregulated at the migrating epidermal edge, although cell growth was not altered. Of the members of the EGF family, HB-EGF mRNA expression was induced the most rapidly and dramatically as a result of scraping in vitro. Combined, these findings clearly demonstrate, for the first time, that HB-EGF is the predominant growth factor involved in epithelialization in skin wound healing in vivo and that it functions by accelerating keratinocyte migration, rather than proliferation.

Key words: Conditional knockout, HB-EGF, Keratinocytes, Migration, Wound healing

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