Upregulation of TGF-beta1 expression may be necessary but is not sufficient for excessive scarring.
Transforming growth factor beta 1 (TGF-beta1) 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-beta1 in fibroblasts and characterized its role. Normal human dermal fibroblasts were genetically modified to overexpress TGF-beta1 as the wild-type latent molecule or as a mutant constitutively active molecule. TGF-beta1 secretion was measured, as were the effects of TGF-beta1 upregulation on cell proliferation, expression of smooth muscle cell alpha actin (SMC alpha-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 approximately 20 times the TGF-beta1 released by control cells, but only cells expressing mutant TGF-beta1 secreted it in the active form. Fibroblasts expressing the active TGF-beta1 gene had increased levels of SMC alpha-actin and enhanced ability to contract a collagen lattice. After intradermal injection into athymic mice, only fibroblasts expressing active TGF-beta1 formed "keloid-like" nodules containing collagen, which persisted longer than implants of the other cell types. We conclude that upregulation of TGF-beta1 by fibroblasts may be necessary, but is not sufficient for excessive scarring. Needed are other signals to activate TGF-beta1 and prolong cell persistence.
Department of Molecular Pharmacology, Physiology and Biotechnology, Biomed Center, Brown University, 171 Meeting Street, Providence, RI 02912, USA.
Anelisa B
AB
Campaner
Lydia M
LM
Ferreira
Alfredo
A
Gragnani
Jan M
JM
Bruder
Jennifer L
JL
Cusick
Jeffrey R
JR
Morgan
D000199:Actins / Q000096:biosynthesis; D000818:Animals; D049109:Cell Proliferation; D002478:Cells, Cultured; D017439:Cicatrix, Hypertrophic / Q000209:etiology* / Q000628:therapy; D005347:Fibroblasts / Q000502:physiology; D006801:Humans; D007627:Keloid / Q000209:etiology* / Q000628:therapy; D051379:Mice; D008819:Mice, Nude; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000502:physiology*; D053773:Transforming Growth Factor beta1; D015854:Up-Regulation
D000199:Actins; C508960:TGFB1 protein, human; C508961:Tgfb1 protein, mouse; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1