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Updated: May 19, 2026

Isolation, Culture, and Characterization of Primary Dermal Fibroblasts from Human Keloid Tissue
Published on: July 28, 2023
Overexpression of hepatocyte growth factor receptor in scleroderma dermal fibroblasts is caused by autocrine
I Kajihara1, M Jinnin, T Makino
1Department of Dermatology and Plastic Surgery, Kumamoto University, Kumamoto, Japan.
Abstract:
Cutaneous fibrosis seen in systemic sclerosis (SSc) is caused by fibroblast activation and abnormal collagen accumulation due to 'autocrine transforming growth factor (TGF)-β/Smad signaling'. Hepatocyte growth factor (HGF) may have therapeutic value against SSc, because of its inducible effect on the expression of matrix metalloproteinase (MMP)-1. Previous studies indicated SSc dermal fibroblasts overexpress HGF receptor c-met, which suggest specific and effective induction of MMP-1 in SSc fibroblasts caused by HGF treatment. However, the exact mechanism of c-met overexpression in SSc cells was hardly investigated. We hypothesized that such c-met overexpression is also caused by autocrine TGF-β/Smad signaling. Expression of c-met protein in cultured SSc dermal fibroblasts was significantly up-regulated compared with that in normal fibroblasts. Ectopic TGF-β stimulation induced c-met synthesis in normal fibroblasts, while a TGF-β knockdown normalized the up-regulated c-met levels in SSc fibroblasts. Furthermore, we found the c-met promoter contains a putative binding site for Smads, and the binding activity of Smad2/3 to the c-met promoter was constitutively up-regulated in SSc fibroblasts as well as in normal fibroblasts treated with exogenous TGF-β1. Taken together, c-met may be overexpressed due to autocrine TGF-β/Smad signaling in SSc. Considering that HGF has an antifibrotic effect, such c-met overexpression in SSc fibroblasts may be a negative feedback against cutaneous fibrosis. Clarifying the mechanisms of c-met overexpression and controlling the HGF/c-met pathway may lead to a new therapeutic approach for this disease.
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