title: Three-dimensional tissue structure affects sensitivity of fibroblasts to TGF-beta 1.
abstract: Transforming growth factor-beta (TGF-beta) is known to induce alpha-smooth muscle actin (alpha-SMA) in fibroblasts and is supposed to play a role in myofibroblast differentiation and tumor desmoplasia. Our objective was to elucidate the impact of TGF-beta1 on alpha-SMA expression in fibroblasts in a three-dimensional (3-D) vs. two-dimensional (2-D) environment. In monolayer culture, all fibroblast cultures responded in a similar fashion to TGF-beta1 with regard to alpha-SMA expression. In fibroblast spheroids, alpha-SMA expression was reduced and induction by TGF-beta1 was highly variable. This difference correlated with a differential regulation in the TGF-beta receptor (TGFbetaR) expression, in particular with a reduction in TGF-betaRII in part of the fibroblast types. Our data indicate that 1) sensitivity to TGF-beta1-induced alpha-SMA expression in a 3-D environment is fibroblast-type specific, 2) fibroblast type-independent regulatory mechanisms, such as a general reduction/loss in TGF-betaRIII, contribute to an altered TGFbetaR expression profile in spheroid compared with monolayer culture, and 3) fibroblast type-specific alterations in TGFbetaR types I and II determine the sensitivity to TGF-beta1-induced alpha-SMA expression in the 3-D setting. We suggest that fibroblasts that can be induced by TGF-beta1 to produce alpha-SMA in spheroid culture reflect a "premyofibroblastic" phenotype.
authors.affiliation: Institute of Pathology, University of Regensburg, Franz-Josef-Strauss-Allee 11, D-93042 Regensburg, Germany. leoni.kunz-schughart@med.uni-regensburg.de
authors.forename: Leoni A
authors.initials: LA
authors.lastname: Kunz-Schughart
authors.forename: Sabine
authors.initials: S
authors.lastname: Wenninger
authors.forename: Thomas
authors.initials: T
authors.lastname: Neumeier
authors.forename: Paula
authors.initials: P
authors.lastname: Seidl
authors.forename: Ruth
authors.initials: R
authors.lastname: Knuechel
mesh_terms: D000199:Actins / Q000096:biosynthesis; D002452:Cell Count / Q000379:methods; D018929:Cell Culture Techniques / Q000379:methods; D048429:Cell Size / Q000502:physiology; D002478:Cells, Cultured; D005260:Female; D005347:Fibroblasts / Q000166:cytology* / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D018125:Receptors, Transforming Growth Factor beta / Q000096:biosynthesis; D016212:Transforming Growth Factor beta / Q000494:pharmacology* / Q000502:physiology; D053773:Transforming Growth Factor beta1
chemical_list: D000199:Actins; D018125:Receptors, Transforming Growth Factor beta; C508960:TGFB1 protein, human; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1