Proteolytic and Non-proteolytic Activation of Keratinocyte-Derived Latent TGF-β1 Induces Fibroblast Differentiation in a Wound-Healing Model Using Rat Skin

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  • Hata Shozaburo
    Department of Oral Growth & Development, Fukuoka Dental College, Japan
  • Okamura Kazuhiko
    Department of Morphological Biology, Fukuoka Dental College, Japan
  • Hatta Mitsutoki
    Department of Physiological Science & Molecular Biology, Fukuoka Dental College, Japan
  • Ishikawa Hiroyuki
    Department of Oral Growth & Development, Fukuoka Dental College, Japan
  • Yamazaki Jun
    Department of Physiological Science & Molecular Biology, Fukuoka Dental College, Japan

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  • Proteolytic and Non-proteolytic Activation of Keratinocyte-Derived Latent TGF-<i>β</i>1 Induces Fibroblast Differentiation in a Wound-Healing Model Using Rat Skin

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Transforming growth factor-β1 (TGF-β1) reportedly causes the differentiation of fibroblasts to myofibroblasts during wound healing. We investigated the mechanism underlying the activation of latent TGF-β1 released by keratinocytes in efforts to identify promising pharmacological approaches for the prevention of hypertrophic scar formation. A three-dimensional collagen gel matrix culture was prepared using rat keratinocytes and dermal fibroblasts. Stratified keratinocytes promoted the TGF receptor–dependent increase in α-smooth muscle actin (α-SMA) immunostaining and mRNA levels in fibroblasts. Latent TGF-β1 was found to be localized suprabasally and secreted. α-SMA expression was inhibited by an anti-αv-integrin antibody and a matrix metalloproteinase (MMP) inhibitor, GM6001. In a two-dimensional fibroblast culture, α-SMA expression depended on the production of endogenous TGF-β1 and required αv-integrin or MMP for the response to recombinant latent TGF-β1. In keratinocyte-conditioned medium, MMP-dependent latent TGF-β1 secretion was detected. Applying this medium to the fibroblast culture enhanced α-SMA production. This effect was decreased by GM6001, the anti-αv-integrin antibody, or the preabsorption of latent TGF-β1. These results indicate that keratinocytes secrete latent TGF-β1, which is liberated to fibroblasts over distance and is activated to produce α-SMA with the aid of a positive-feedback loop. MMP inhibition was effective for targeting both keratinocytes and fibroblasts in this model.

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