Upregulation of TGF-β1 Expression May Be Necessary but Is Not Sufficient for Excessive Scarring

Transforming growth factor beta 1 (TGF-β1) upregulation has been implicated in hypertrophic scars and keloids, but it is unclear if it is the cause or an effect of excessive scar formation. In this study, we overexpressed TGF-β1 in fibroblasts and characterized its role. Normal human dermal fibroblasts were genetically modified to overexpress TGF-β1 as the wild-type latent molecule or as a mutant constitutively active molecule. TGF-β1 secretion was measured, as were the effects of TGF-β1 upregulation on cell proliferation, expression of smooth muscle cell alpha actin (SMC α-actin) and ability to contract collagen lattices. Fibroblasts were implanted intradermally into athymic mice and tissue formation was analyzed over time by histology and immunostaining. Gene-modified fibroblasts secreted ∼20 times the TGF-β1 released by control cells, but only cells expressing mutant TGF-β1 secreted it in the active form. Fibroblasts expressing the active TGF-β1 gene had increased levels of SMC α-actin and enhanced ability to contract a collagen lattice. After intradermal injection into athymic mice, only fibroblasts expressing active TGF-β1 formed “keloid-like” nodules containing collagen, which persisted longer than implants of the other cell types. We conclude that upregulation of TGF-β1 by fibroblasts may be necessary, but is not sufficient for excessive scarring. Needed are other signals to activate TGF-β1 and prolong cell persistence.