title: Sulfated glycosaminoglycans and non-classically secreted proteins, basic FGF and epimorphin, coordinately regulate TGF-β-induced cell behaviors of human scar dermal fibroblasts.
abstract: BACKGROUND
  Upon skin injuries, dermal fibroblasts actively produce transforming growth factor-β (TGF-β), which leads to the formation of α-smooth muscle actin (αSMA)-positive granulation tissues. The hyperplasia or incomplete regression of these tissues subsequently causes scar formation in the skin, where sulfated glycosaminoglycans (GAGs), side chains of unique proteoglycans, are supposed to play important roles.
  
  
  OBJECTIVE
  The aim of this study is to clarify the effects of sulfated GAGs on dermal cell behaviors triggered by the TGF-β signaling, along with its possible regulators basic fibroblast growth factor (bFGF) and cell surface epimorphin. bFGF and epimorphin might regulate the TGF-β-induced αSMA expression, they could exert such effects only in specific cellular contexts, given that they lack conventional signal sequences for extracellular localization.
  
  
  METHODS
  Human scar-derived dermal fibroblasts (HSFs) were treated with TGF-β alone, TGF-β plus bFGF, and TGF-β plus cell surface expression of epimorphin. The effects of GAGs on the expression of αSMA and the cellular morphology were then investigated.
  
  
  RESULTS
  A highly sulfated chondroitin sulfate (CS-E) or its substitute (heparinoid) had marked inhibitory effects on TGF-β-mediated changes in HSF behaviors. We found that heparinoid can directly associate with TGF-β, bFGF and epimorphin. We also found that bFGF downregulated αSMA, which was attenuated by heparinoid, whereas epimorphin augmented αSMA expression, which was further amplified by heparinoid.
  
  
  CONCLUSIONS
  TGF-β, bFGF and epimorphin in the extracellular microenvironment cooperatively affect HSF behaviors under the control of a highly sulfated chondroitin sulfate. These results provide important evidence towards understanding the regulation of TGF-β-induced HSF behaviors.
authors.affiliation: Department of Biomedical Chemistry, Graduate school of Science and Technology, Kwansei Gakuin University, 2-1, Gakuen, Sanda 669-1337, Japan.
authors.forename: Tomoatsu
authors.initials: T
authors.lastname: Horigome
authors.affiliation: R&D Healthcare Division, Kobayashi Pharmaceutical Co. LTD, 1-30-3, Toyokawa, Ibaraki 567-0057, Japan.
authors.forename: Shinya
authors.initials: S
authors.lastname: Takumi
authors.affiliation: Department of Biomedical Chemistry, Graduate school of Science and Technology, Kwansei Gakuin University, 2-1, Gakuen, Sanda 669-1337, Japan.
authors.forename: Kota
authors.initials: K
authors.lastname: Shirai
authors.affiliation: Department of Biomedical Chemistry, Graduate school of Science and Technology, Kwansei Gakuin University, 2-1, Gakuen, Sanda 669-1337, Japan.
authors.forename: Takumi
authors.initials: T
authors.lastname: Kido
authors.affiliation: Department of Biomedical Chemistry, Graduate school of Science and Technology, Kwansei Gakuin University, 2-1, Gakuen, Sanda 669-1337, Japan.
authors.forename: Natsumi
authors.initials: N
authors.lastname: Hagiwara-Chatani
authors.affiliation: R&D Healthcare Division, Kobayashi Pharmaceutical Co. LTD, 1-30-3, Toyokawa, Ibaraki 567-0057, Japan.
authors.forename: Ayumi
authors.initials: A
authors.lastname: Nakashima
authors.affiliation: Department of Biomedical Chemistry, Graduate school of Science and Technology, Kwansei Gakuin University, 2-1, Gakuen, Sanda 669-1337, Japan.
authors.forename: Naoki
authors.initials: N
authors.lastname: Adachi
authors.affiliation: R&D Healthcare Division, Kobayashi Pharmaceutical Co. LTD, 1-30-3, Toyokawa, Ibaraki 567-0057, Japan.
authors.forename: Hiroko
authors.initials: H
authors.lastname: Yano
authors.affiliation: Department of Biomedical Chemistry, Graduate school of Science and Technology, Kwansei Gakuin University, 2-1, Gakuen, Sanda 669-1337, Japan. Electronic address: y-hirai@kwansei.ac.jp.
authors.forename: Yohei
authors.initials: Y
authors.lastname: Hirai
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D019556:COS Cells; D002462:Cell Membrane / Q000378:metabolism; D002522:Chlorocebus aethiops; D002809:Chondroitin Sulfates / Q000737:chemistry; D002921:Cicatrix / Q000378:metabolism*; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology; D005347:Fibroblasts / Q000378:metabolism*; D006025:Glycosaminoglycans / Q000737:chemistry*; D006496:Heparinoids / Q000378:metabolism; D006801:Humans; D011509:Proteoglycans / Q000378:metabolism*; D011994:Recombinant Proteins / Q000494:pharmacology; D015398:Signal Transduction; D013552:Swine; D050827:Syntaxin 1 / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000494:pharmacology*
chemical_list: D000199:Actins; D006025:Glycosaminoglycans; D006496:Heparinoids; D011509:Proteoglycans; D011994:Recombinant Proteins; C074558:STX2 protein, human; D050827:Syntaxin 1; D016212:Transforming Growth Factor beta; D016222:Fibroblast Growth Factor 2; D002809:Chondroitin Sulfates
keywords: Alpha smooth muscle actin; Epimorphin; Glycosaminoglycan; Heparinoid; Scar; bFGF