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

Abstract

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.

Keloids: Current concepts of pathogenesis (Review)

“…TGF-ß is a well acknowledged growth factor in keloid formation with extensive scientific focus being placed on this pathway. Interestingly, a recent study by Campaner and coworkers (98) reported that overexpression of TGF-ß1 is an important component in the formation of keloid tissue, but is not as sufficient as an independent factor, providing evidence for the hypothesis that keloid formation is a multifactorial process (38).…”

Development, validation and testing of a human tissue engineered hypertrophic scar model

“…Also, neuro-endocrine signals (Ferreira et al, 2009) and an angiogenic component have not yet been incorporated in this HTscar model. Also, extensive screening for more parameters, such as increased TGFβ1 (Campaner et al, 2006) or CTGF (Moon et al, 2012), might further improve the model and provide more insight into human HTscar formation. Another limitation is that only therapeutics that can be dissolved in the culture medium have been studied.…”

ILK–PI3K/AKT pathway participates in cutaneous wound contraction by regulating fibroblast migration and differentiation to myofibroblast

“…42 Fibroblasts overexpressing the TGF-β 1 gene increase α-SMA expression and enhance FPCL contraction, and the TGF-β/ Smad pathway is involved in inducing α-SMA expression. 18,43 α-SMA is characteristically expressed by myofibroblasts in the skin and is considered a marker of differentiation of fibroblasts to myofibroblasts. Myofibroblast differentiation is widely considered a crucial factor contributing to wound and scar contraction.…”

“…It contributes to wound contraction. 18 Recent studies suggest that ILK is a key intracellular mediator in the 'crosstalk' between an integrin and the TGF-β 1 pathway. ILK overexpression promotes α-SMA expression as well as epithelial-mesenchymal transition (EMT) in renal tubular epithelial cells.…”